Polypeptides from non-typeable haemophilus influenzae

ABSTRACT

Polypeptides comprising non-typeable  Haemophilus influenzae  (NTHi) amino acid sequences. Over 2500 specific NTHi proteins are disclosed. The invention also provides related polypeptides, nucleic acids, antibodies and methods. These can all be usedin medicine for treating or preventing disease and/or infection caused by  H. influenzae , such as otitis media.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 13/357,394, filed Jan. 24, 2012, which is a divisional of U.S. patent application Ser. No. 12/800,898, filed May 25, 2010, now U.S. Pat. No. 8,124,098, which is a continuation of U.S. patent application Ser. No. 11/596,557, filed Feb. 14, 2008, now U.S. Pat. No. 7,749,518, which is a 371 of PCT/IB05/01775, filed May 16, 2005, and claims priority to United Kingdom patent application no. 0410866.8, filed May 14, 2004, from which applications priority is claimed pursuant to 35 U.S.C. §§119/120 and which applications are incorporated herein by reference in their entireties.

INCORPORATION BY REFERENCE OF MATERIAL ON COMPACT DISC

This application incorporates by reference the Sequence Listing contained on the two compact discs (Copy 1 and Copy 2), filed concurrently herewith, containing the following file:

File name: PP022930.0003 SequenceList.txt; created Nov. 10, 2006; 6,676 KB in size.

TECHNICAL FIELD

This invention is in the field of Haemophilus influenzae immunology and vaccinology.

BACKGROUND ART

Haemophilus influenzae is a small, non-motile, Gram-negative coccobacillus. It is a respiratory pathogen that causes a wide spectrum of human infections, including: asymptomatic colonization of the upper respiratory tract (i.e. carriage); infections that extend from colonized mucosal surfaces to cause otitis media (inflammation of the middle ear), bronchitis, conjunctivitis, sinusitis, urinary tract infections and pneumonia; and invasive infections, such as bacteremia, septic arthritis, epiglottitis, pneumonia, empyema, pericarditis, cellulitis, osteomyelitis and meningitis. H. influenzae was the first bacterium for which a complete genome sequence was published [1].

H. influenzae strains are either capsulated (typeable) or non-capsulated (non-typeable), and there are six major serological types of capsulated strains (a to f). 95% of H. influenzae-caused invasive diseases are caused by H. influenzae type b (‘Hib’) strains. The most serious manifestation of Hib disease is meningitis, but the introduction in the 1980s of vaccines based on conjugated Hib capsular saccharides has hugely reduced incidence of this disease.

Although Hib infections can now be controlled by vaccination, other pathogenic H. influenzae strains remain a risk. For instance, non-typeable H. influenzae (NTHi) is responsible for otitis media (OM), particularly chronic OM. While OM is rarely associated with mortality, it is associated with significant morbidity. Hearing loss is the most common complication of OM, with behavioral, educational and language development delays being additional consequences of early onset OM with effusion. Acute OM is the most common bacterial infection in children in the USA. The non-typeable H. influenzae biogroup aegyptius causes epidemic conjunctivitis and Brazilian purpuric fever (BPF) [2], with BPF having a mortality of up to 70%.

To date, antibiotics are the main tool against the spectrum of clinical entities known collectively as OM, but widespread use of antibiotics for OM has met with controversy due to the emergence of multiple-antibiotic resistant microorganisms. Progress towards a vaccine is slow due to an incomplete understanding of both the pathogenesis of OM and the immune response to it.

The genome sequence of the serotype d strain KW20 [1,3] has been useful for understanding basic H. influenzae biology, but it has not been so useful in countering pathogenic H. influenzae strains, as serotype d strains are generally not pathogens.

It is an object of the invention to provide polypeptides for use in the development of vaccines for preventing and/or treating infections caused by non-typeable H. influenzae strains. In particular, it is an object to provide polypeptides for use in improved vaccines for preventing and/or treating otitis media. The polypeptides may also be useful for diagnostic purposes, and as targets for antibiotics.

DISCLOSURE OF THE INVENTION Polypeptides

The invention provides polypeptides comprising the H. influenzae amino acid sequences disclosed in the examples. These amino acid sequences are the even SEQ ID NOs between 2 and 5080. There are thus 2540 amino acid sequences, and these are referred to as NTHnnnn, where nnnn is a number between 0001 and 2832 (there are 292 NTHnnnn numbers that have no sequence; see Table I). Further NTHi sequences of the invention are given as SEQ ID NOS: 5088 onwards.

The invention also provides polypeptides comprising amino acid sequences that have sequence identity to the H. influenzae amino acid sequences disclosed in the examples. Depending on the particular sequence, the degree of sequence identity is preferably greater than 50% (e.g. 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more). These polypeptides include homologs, orthologs, allelic variants and functional mutants. Typically, 50% identity or more between two polypeptide sequences is considered to be an indication of functional equivalence. Identity between polypeptides is preferably determined by the Smith-Waterman homology search algorithm as implemented in the MPSRCH program (Oxford Molecular), using an affine gap search with parameters gap open penalty=12 and gap extension penalty=1.

These polypeptide may, compared to the NTHi sequences of the examples, include one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) conservative amino acid replacements i.e. replacements of one amino acid with another which has a related side chain. Genetically-encoded amino acids are generally divided into four families: (1) acidic i.e. aspartate, glutamate; (2) basic i.e. lysine, arginine, histidine; (3) non-polar i.e. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar i.e. glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In general, substitution of single amino acids within these families does not have a major effect on the biological activity. The polypeptides may also include one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) single amino acid deletions relative to the NTHi sequences of the examples. The polypeptides may also include one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) insertions (e.g. each of 1, 2, 3, 4 or 5 amino acids) relative to the NTHi sequences of the examples.

Preferred polypeptides of the invention are listed in Table II, including polypeptides that are lipidated, that are located in the outer membrane, that are located in the inner membrane, that are located in the periplasm, or that are not found in non-pathogenic H. influenzae strains. Particularly preferred polypeptides are those that fall into more than one of these categories e.g. polypeptides that are located in the outer membrane and are also not found in non-pathogenic H. influenzae strains.

A particularly preferred polypeptide is NTH0867. NTH0861, NTH0863 and NTH0865 are also preferred. As described below, these four proteins are embodied by SEQ ID NOS: 1566, 5095, 1570, 5094, 1574, 5093, 1578 and 5092. Within these eight SEQ ID NOS, 1566-1578 are preferred.

The invention further provides polypeptides comprising fragments of the H. influenzae amino acid sequences disclosed in the examples. The fragments should comprise at least n consecutive amino acids from the sequences and, depending on the particular sequence, n is 7 or more (e.g. 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or more).

The fragment may comprise at least one T-cell or, preferably, a B-cell epitope of the sequence. T- and B-cell epitopes can be identified empirically (e.g. using PEPSCAN [4,5] or similar methods), or they can be predicted (e.g. using the Jameson-Wolf antigenic index [6], matrix-based approaches [7], TEPITOPE [8], neural networks [9], OptiMer & EpiMer [10, 11], ADEPT [12], Tsites [13], hydrophilicity [14], antigenic index [15] or the methods disclosed in reference 16 etc.). Other preferred fragments are (a) the N-terminal signal peptides of the NTHi polypeptides of the invention, (b) the NTHi polypeptides, but without their N-terminal signal peptides, (c) the NTHi polypeptides, but without their N-terminal amino acid residue.

Polypeptides of the invention can be prepared in many ways e.g. by chemical synthesis (in whole or in part), by digesting longer polypeptides using proteases, by translation from RNA, by purification from cell culture (e.g. from recombinant expression), from the organism itself (e.g. after bacterial culture, or direct from patients), etc. A preferred method for production of peptides <40 amino acids long involves in vitro chemical synthesis [17,18]. Solid-phase peptide synthesis is particularly preferred, such as methods based on tBoc or Fmoc [19] chemistry. Enzymatic synthesis [20] may also be used in part or in full. As an alternative to chemical synthesis, biological synthesis may be used e.g. the polypeptides may be produced by translation. This may be carried out in vitro or in vivo.

Biological methods are in general restricted to the production of polypeptides based on L-amino acids, but manipulation of translation machinery (e.g. of aminoacyl tRNA molecules) can be used to allow the introduction of D-amino acids (or of other non natural amino acids, such as iodotyrosine or methylphenylalanine, azidohomoalanine, etc.) [21]. Where D-amino acids are included, however, it is preferred to use chemical synthesis. Polypeptides of the invention may have covalent modifications at the C-terminus and/or N-terminus.

Polypeptides of the invention can take various forms (e.g. native, fusions, glycosylated, non-glycosylated, lipidated, non-lipidated, phosphorylated, non-phosphorylated, myristoylated, non-myristoylated, monomeric, multimeric, particulate, denatured, etc.).

Polypeptides of the invention are preferably provided in purified or substantially purified form i.e. substantially free from other polypeptides (e.g. free from naturally-occurring polypeptides), particularly from other Haemophilus or host cell polypeptides, and are generally at least about 50% pure (by weight), and usually at least about 90% pure i.e. less than about 50%, and more preferably less than about 10% (e.g. 5%) of a composition is made up of other expressed polypeptides.

Polypeptides of the invention are preferably H. influenzae polypeptides. Polypeptides of the invention preferably have the function indicated in Table III for the relevant sequence.

Polypeptides of the invention may be attached to a solid support. Polypeptides of the invention may comprise a detectable label (e.g. a radioactive or fluorescent label, or a biotin label).

The term “polypeptide” refers to amino acid polymers of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. Polypeptides can occur as single chains or associated chains. Polypeptides of the invention can be naturally or non-naturally glycosylated (i.e. the polypeptide has a glycosylation pattern that differs from the glycosylation pattern found in the corresponding naturally occurring polypeptide).

The invention provides polypeptides comprising a sequence —X—Y— or —Y—X—, wherein: —X— is an amino acid sequence as defined above and —Y— is not a sequence as defined above i.e. the invention provides fusion proteins. Where the N-terminus codon of a polypeptide-coding sequence is not ATG then that codon will be translated as the standard amino acid for that codon rather than as a Met, which occurs when the codon is a start codon.

The invention provides a process for producing polypeptides of the invention, comprising the step of culturing a host cell of to the invention under conditions which induce polypeptide expression.

The invention provides a process for producing a polypeptide of the invention, wherein the polypeptide is synthesised in part or in whole using chemical means.

The invention provides a composition comprising two or more polypeptides of the invention.

The invention also provides a hybrid polypeptide represented by the formula NH₂-A-[-X-L-]_(n)-B—COOH, wherein X is a polypeptide of the invention as defined above, L is an optional linker amino acid sequence, A is an optional N-terminal amino acid sequence, B is an optional C-terminal amino acid sequence, and n is an integer greater than 1. The value of n is between 2 and x, and the value of x is typically 3, 4, 5, 6, 7, 8, 9 or 10. Preferably n is 2, 3 or 4; it is more preferably 2 or 3; most preferably, n=2. For each n instances, —X— may be the same or different. For each n instances of [—X-L-], linker amino acid sequence -L- may be present or absent. For instance, when n=2 the hybrid may be NH₂—X₁-L₁-X₂-L₂-COOH, NH₂—X₁—X₂—COOH, NH₂—X₁-L₁-X₂—COOH, NH₂—X₁—X₂-L₂-COOH, etc. Linker amino acid sequence(s) -L- will typically be short (e.g. 20 or fewer amino acids i.e. 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include short peptide sequences which facilitate cloning, poly-glycine linkers (i.e. Gly_(n) where n=2, 3, 4, 5, 6, 7, 8, 9, 10 or more), and histidine tags (i.e. His_(n) where n=3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable linker amino acid sequences will be apparent to those skilled in the art. -A- and —B— are optional sequences which will typically be short (e.g. 40 or fewer amino acids i.e. 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include leader sequences to direct polypeptide trafficking, or short peptide sequences which facilitate cloning or purification (e.g. histidine tags i.e. His_(n) where n=3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable N-terminal and C-terminal amino acid sequences will be apparent to those skilled in the art.

Various tests can be used to assess the in vivo immunogenicity of polypeptides of the invention. For example, polypeptides can be expressed recombinantly and used to screen patient sera by immunoblot. A positive reaction between the polypeptide and patient serum indicates that the patient has previously mounted an immune response to the protein in question i.e. the protein is an immunogen. This method can also be used to identify immunodominant proteins.

Antibodies

The invention provides antibodies that bind to polypeptides of the invention. These may be polyclonal or monoclonal and may be produced by any suitable means (e.g. by recombinant expression). To increase compatibility with the human immune system, the antibodies may be chimeric or humanised [e.g. refs. 22 & 23], or fully human antibodies may be used. The antibodies may include a detectable label (e.g. for diagnostic assays). Antibodies of the invention may be attached to a solid support. Antibodies of the invention are preferably neutralizing antibodies.

Monoclonal antibodies are particularly useful in identification and purification of the individual polypeptides against which they are directed. Monoclonal antibodies of the invention may also be employed as reagents in immunoassays, radioimmunoassays (RIA) or enzyme-linked immunosorbent assays (ELISA), etc. In these applications, the antibodies can be labelled with an analytically-detectable reagent such as a radioisotope, a fluorescent molecule or an enzyme. The monoclonal antibodies produced by the above method may also be used for the molecular identification and characterization (epitope mapping) of polypeptides of the invention.

Antibodies of the invention are preferably provided in purified or substantially purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides e.g. where less than 90% (by weight), usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides.

Antibodies of the invention can be of any isotype (e.g. IgA, IgG, IgM i.e. an α, γ or μ heavy chain), but will generally be IgG. Within the IgG isotype, antibodies may be IgG1, IgG2, IgG3 or IgG4 subclass. Antibodies of the invention may have a κ or a λ light chain.

Antibodies of the invention can take various forms, including whole antibodies, antibody fragments such as F(ab′)2 and F(ab) fragments, Fv fragments (non-covalent heterodimers), single-chain antibodies such as single chain Fv molecules (scFv), minibodies, oligobodies, etc. The term “antibody” does not imply any particular origin, and includes antibodies obtained through non-conventional processes, such as phage display.

The invention provides a process for detecting polypeptides of the invention, comprising the steps of: (a) contacting an antibody of the invention with a biological sample under conditions suitable for the formation of an antibody-antigen complexes; and (b) detecting said complexes.

The invention provides a process for detecting antibodies of the invention, comprising the steps of (a) contacting a polypeptide of the invention with a biological sample (e.g. a blood or serum sample) under conditions suitable for the formation of an antibody-antigen complexes; and (b) detecting said complexes.

Nucleic Acids

The invention provides nucleic acid comprising the H. influenzae nucleotide sequences disclosed in the examples. These nucleic acid sequences are the odd SEQ ID NOs between 1 and 5080.

The invention also provides nucleic acid comprising nucleotide sequences having sequence identity to the H. influenzae nucleotide sequences disclosed in the examples. Identity between sequences is preferably determined by the Smith-Waterman homology search algorithm as described above.

The invention also provides nucleic acid which can hybridize to the H. influenzae nucleic acid disclosed in the examples. Hybridization reactions can be performed under conditions of different “stringency”. Conditions that increase stringency of a hybridization reaction of widely known and published in the art [e.g. page 7.52 of reference 24]. Examples of relevant conditions include (in order of increasing stringency): incubation temperatures of 25° C., 37° C., 50° C., 55° C. and 68° C.; buffer concentrations of 10×SSC, 6×SSC, 1×SSC, 0.1×SSC (where SSC is 0.15 M NaCl and 15 mM citrate buffer) and their equivalents using other buffer systems; formamide concentrations of 0%, 25%, 50%, and 75%; incubation times from 5 minutes to 24 hours; 1, 2, or more washing steps; wash incubation times of 1, 2, or 15 minutes; and wash solutions of 6×SSC, 1×SSC, 0.1×SSC, or de-ionized water. Hybridization techniques and their optimization are well known in the art [e.g. see references 24-27, etc.].

In some embodiments, nucleic acid of the invention hybridizes to a target of the invention under low stringency conditions; in other embodiments it hybridizes under intermediate stringency conditions; in preferred embodiments, it hybridizes under high stringency conditions. An exemplary set of low stringency hybridization conditions is 50° C. and 10×SSC. An exemplary set of intermediate stringency hybridization conditions is 55° C. and 1×SSC. An exemplary set of high stringency hybridization conditions is 68° C. and 0.1×SSC.

Nucleic acid comprising fragments of these sequences are also provided. These should comprise at least n consecutive nucleotides from the H. influenzae sequences and, depending on the particular sequence, n is 10 or more (e.g. 12, 14, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200 or more).

The invention provides nucleic acid of formula 5′-X—Y—Z-3′, wherein: —X— is a nucleotide sequence consisting of x nucleotides; —Z— is a nucleotide sequence consisting of z nucleotides; —Y— is a nucleotide sequence consisting of either (a) a fragment of one of the odd-numbered SEQ ID NOS: 1 to 5079, or (b) the complement of (a); and said nucleic acid 5′-X—Y—Z-3′ is neither (i) a fragment of one of the odd-numbered SEQ ID NOS: 1 to 5079 nor (ii) the complement of (i). The —X— and/or —Z— moieties may comprise a promoter sequence (or its complement).

The invention also provides nucleic acid encoding the polypeptides and polypeptide fragments of the invention.

The invention includes nucleic acid comprising sequences complementary to the sequences disclosed in the sequence listing (e.g. for antisense or probing, or for use as primers), as well as the sequences in the orientation actually shown.

Nucleic acids of the invention can be used in hybridisation reactions (e.g. Northern or Southern blots, or in nucleic acid microarrays or ‘gene chips’) and amplification reactions (e.g. PCR, SDA, SSSR, LCR, TMA, NASBA, etc.) and other nucleic acid techniques.

Nucleic acid according to the invention can take various forms (e.g. single-stranded, double-stranded, vectors, primers, probes, labelled etc.). Nucleic acids of the invention may be circular or branched, but will generally be linear. Unless otherwise specified or required, any embodiment of the invention that utilizes a nucleic acid may utilize both the double-stranded form and each of two complementary single-stranded forms which make up the double-stranded form. Primers and probes are generally single-stranded, as are antisense nucleic acids.

Nucleic acids of the invention are preferably provided in purified or substantially purified form i.e. substantially free from other nucleic acids (e.g. free from naturally-occurring nucleic acids), particularly from other Haemophilus or host cell nucleic acids, generally being at least about 50% pure (by weight), and usually at least about 90% pure. Nucleic acids of the invention are preferably H. influenzae nucleic acids.

Nucleic acids of the invention may be prepared in many ways e.g. by chemical synthesis (e.g. phosphoramidite synthesis of DNA) in whole or in part, by digesting longer nucleic acids using nucleases (e.g. restriction enzymes), by joining shorter nucleic acids or nucleotides (e.g. using ligases or polymerases), from genomic or cDNA libraries, etc.

Nucleic acid of the invention may be attached to a solid support (e.g. a bead, plate, filter, film, slide, microarray support, resin, etc.). Nucleic acid of the invention may be labelled e.g. with a radioactive or fluorescent label, or a biotin label. This is particularly useful where the nucleic acid is to be used in detection techniques e.g. where the nucleic acid is a primer or as a probe.

The term “nucleic acid” includes in general means a polymeric form of nucleotides of any length, which contain deoxyribonucleotides, ribonucleotides, and/or their analogs. It includes DNA, RNA, DNA/RNA hybrids. It also includes DNA or RNA analogs, such as those containing modified backbones (e.g. peptide nucleic acids (PNAs) or phosphorothioates) or modified bases. Thus the invention includes mRNA, tRNA, rRNA, ribozymes, DNA, cDNA, recombinant nucleic acids, branched nucleic acids, plasmids, vectors, probes, primers, etc. Where nucleic acid of the invention takes the form of RNA, it may or may not have a 5′ cap.

Nucleic acids of the invention comprise NTHi sequences, but they may also comprise non-NTHi sequences (e.g. in nucleic acids of formula 5′-X—Y—Z-3′, as defined above). This is particularly useful for primers, which may thus comprise a first sequence complementary to a PCAV nucleic acid target and a second sequence which is not complementary to the nucleic acid target. Any such non-complementary sequences in the primer are preferably 5′ to the complementary sequences. Typical non-complementary sequences comprise restriction sites or promoter sequences.

Nucleic acids of the invention can be prepared in many ways e.g. by chemical synthesis (at least in part), by digesting longer nucleic acids using nucleases (e.g. restriction enzymes), by joining shorter nucleic acids (e.g. using ligases or polymerases), from genomic or cDNA libraries, etc.

Nucleic acids of the invention may be part of a vector i.e. part of a nucleic acid construct designed for transduction/transfection of one or more cell types. Vectors may be, for example, “cloning vectors” which are designed for isolation, propagation and replication of inserted nucleotides, “expression vectors” which are designed for expression of a nucleotide sequence in a host cell, “viral vectors” which is designed to result in the production of a recombinant virus or virus-like particle, or “shuttle vectors”, which comprise the attributes of more than one type of vector. Preferred vectors are plasmids. A “host cell” includes an individual cell or cell culture which can be or has been a recipient of exogenous nucleic acid. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation and/or change. Host cells include cells transfected or infected in vivo or in vitro with nucleic acid of the invention.

Where a nucleic acid is DNA, it will be appreciated that “U” in a RNA sequence will be replaced by “T” in the DNA. Similarly, where a nucleic acid is RNA, it will be appreciated that “T” in a DNA sequence will be replaced by “U” in the RNA.

The term “complement” or “complementary” when used in relation to nucleic acids refers to Watson-Crick base pairing. Thus the complement of C is G, the complement of G is C, the complement of A is T (or U), and the complement of T (or U) is A. It is also possible to use bases such as I (the purine inosine) e.g. to complement pyrimidines (C or T). The terms also imply a direction—the complement of 5′-ACAGT-3′ is 5′-ACTGT-3′ rather than 5′-TGTCA-3′.

Nucleic acids of the invention can be used, for example: to produce polypeptides; as hybridization probes for the detection of nucleic acid in biological samples; to generate additional copies of the nucleic acids; to generate ribozymes or antisense oligonucleotides; as single-stranded DNA primers or probes; or as triple-strand forming oligonucleotides.

The invention provides a process for producing nucleic acid of the invention, wherein the nucleic acid is synthesised in part or in whole using chemical means.

The invention provides vectors comprising nucleotide sequences of the invention (e.g. cloning or expression vectors) and host cells transformed with such vectors.

The invention also provides a kit comprising primers (e.g. PCR primers) for amplifying a template sequence contained within a Haemophilus bacterium (e.g. H. influenzae) nucleic acid sequence, the kit comprising a first primer and a second primer, wherein the first primer is substantially complementary to said template sequence and the second primer is substantially complementary to a complement of said template sequence, wherein the parts of said primers which have substantial complementarity define the termini of the template sequence to be amplified. The first primer and/or the second primer may include a detectable label (e.g. a fluorescent label).

The invention also provides a kit comprising first and second single-stranded oligonucleotides which allow amplification of a Haemophilus template nucleic acid sequence contained in a single- or double-stranded nucleic acid (or mixture thereof), wherein: (a) the first oligonucleotide comprises a primer sequence which is substantially complementary to said template nucleic acid sequence; (b) the second oligonucleotide comprises a primer sequence which is substantially complementary to the complement of said template nucleic acid sequence; (c) the first oligonucleotide and/or the second oligonucleotide comprise(s) sequence which is not compementary to said template nucleic acid; and (d) said primer sequences define the termini of the template sequence to be amplified. The non-complementary sequence(s) of feature (c) are preferably upstream of (i.e. 5′ to) the primer sequences. One or both of these (c) sequences may comprise a restriction site [e.g. ref.28] or a promoter sequence [e.g. 29]. The first oligonucleotide and/or the second oligonucleotide may include a detectable label (e.g. a fluorescent label).

The template sequence may be any part of a genome sequence.

The invention provides a process for detecting nucleic acid of the invention, comprising the steps of: (a) contacting a nucleic probe according to the invention with a biological sample under hybridising conditions to form duplexes; and (b) detecting said duplexes.

The invention provides a process for detecting H. influenzae in a biological sample (e.g. blood), comprising the step of contacting nucleic acid according to the invention with the biological sample under hybridising conditions. The process may involve nucleic acid amplification (e.g. PCR, SDA, SSSR, LCR, TMA, NASBA, etc.) or hybridisation (e.g. microarrays, blots, hybridisation with a probe in solution etc.). PCR detection of H. influenzae in clinical samples has been reported [e.g. see refs. 30 & 31]. Clinical assays based on nucleic acid are described in general in ref. 32.

The invention provides a process for preparing a fragment of a target sequence, wherein the fragment is prepared by extension of a nucleic acid primer. The target sequence and/or the primer are nucleic acids of the invention. The primer extension reaction may involve nucleic acid amplification (e.g. PCR, SDA, SSSR, LCR, TMA, NASBA, etc.).

Nucleic acid amplification according to the invention may be quantitative and/or real-time.

For certain embodiments of the invention, nucleic acids are preferably at least 7 nucleotides in length (e.g. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300 nucleotides or longer).

For certain embodiments of the invention, nucleic acids are preferably at most 500 nucleotides in length (e.g. 450, 400, 350, 300, 250, 200, 150, 140, 130, 120, 110, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15 nucleotides or shorter).

Primers and probes of the invention, and other nucleic acids used for hybridization, are preferably between 10 and 30 nucleotides in length (e.g. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides).

Pharmaceutical Compositions

The invention provides compositions comprising: (a) polypeptide, antibody, and/or nucleic acid of the invention; and (b) a pharmaceutically acceptable carrier. These compositions may be suitable as immunogenic compositions, for instance, or as diagnostic reagents, or as vaccines. Vaccines according to the invention may either be prophylactic (i.e. to prevent infection) or therapeutic (i.e. to treat infection), but will typically be prophylactic.

A ‘pharmaceutically acceptable carriers’ includes any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition. Suitable carriers are typically large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, sucrose, trehalose, lactose, and lipid aggregates (such as oil droplets or liposomes). Such carriers are well known to those of ordinary skill in the art. The vaccines may also contain diluents, such as water, saline, glycerol, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present. Sterile pyrogen-free, phosphate-buffered physiologic saline is a typical carrier. A thorough discussion of pharmaceutically acceptable excipients is available in ref. 138.

Compositions of the invention may include an antimicrobial, particularly if packaged in a multiple dose format.

Compositions of the invention may comprise detergent e.g. a Tween (polysorbate), such as Tween 80. Detergents are generally present at low levels e.g. <0.01%.

Compositions of the invention may include sodium salts (e.g. sodium chloride) to give tonicity. A concentration of 10±2 mg/ml NaCl is typical.

Compositions of the invention will generally include a buffer. A phosphate buffer is typical.

Compositions of the invention may comprise a sugar alcohol (e.g. mannitol) or a disaccharide (e.g. sucrose or trehalose) e.g. at around 15-30 mg/ml (e.g. 25 mg/ml), particularly if they are to be lyophilised or if they include material which has been reconstituted from lyophilised material. The pH of a composition for lyophilisation may be adjusted to around 6.1 prior to lyophilisation.

Polypeptides of the invention may be administered in conjunction with other immunoregulatory agents. In particular, compositions will usually include a vaccine adjuvant. Adjuvants which may be used in compositions of the invention include, but are not limited to:

A. Mineral-Containing Compositions

Mineral containing compositions suitable for use as adjuvants in the invention include mineral salts, such as aluminium salts and calcium salts. The invention includes mineral salts such as hydroxides (e.g. oxyhydroxides), phosphates (e.g. hydroxyphosphates, orthophosphates), sulphates, etc. [e.g. see chapters 8 & 9 of ref. 33], or mixtures of different mineral compounds, with the compounds taking any suitable form (e.g. gel, crystalline, amorphous, etc.), and with adsorption being preferred. The mineral containing compositions may also be formulated as a particle of metal salt [34].

Aluminium phosphates are particularly preferred, particularly in compositions which include a H. influenzae saccharide antigen, and a typical adjuvant is amorphous aluminium hydroxyphosphate with PO₄/Al molar ratio between 0.84 and 0.92, included at 0.6 mg Al³⁺/ml. Adsorption with a low dose of aluminium phosphate may be used e.g. between 50 and 100 μg Al³⁺ per conjugate per dose. Where there is more than one conjugate in a composition, not all conjugates need to be adsorbed.

B. Oil Emulsions

Oil emulsion compositions suitable for use as adjuvants in the invention include squalene-water emulsions, such as MF59 [Chapter 10 of ref 33; see also ref. 35] (5% Squalene, 0.5% Tween 80, and 0.5% Span 85, formulated into submicron particles using a microfluidizer). Complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA) may also be used.

C. Saponin Formulations [Chapter 22 of Ref 33]

Saponin formulations may also be used as adjuvants in the invention. Saponins are a heterologous group of sterol glycosides and triterpenoid glycosides that are found in the bark, leaves, stems, roots and even flowers of a wide range of plant species. Saponin from the bark of the Quillaia saponaria Molina tree have been widely studied as adjuvants. Saponin can also be commercially obtained from Smilax ornata (sarsaprilla), Gypsophilla paniculata (brides veil), and Saponaria officianalis (soap root). Saponin adjuvant formulations include purified formulations, such as QS21, as well as lipid formulations, such as ISCOMs. QS21 is marketed as Stimulon™.

Saponin compositions have been purified using HPLC and RP-HPLC. Specific purified fractions using these techniques have been identified, including QS7, QS17, QS18, QS21, QH-A, QH-B and QH-C. Preferably, the saponin is QS21. A method of production of QS21 is disclosed in ref 36. Saponin formulations may also comprise a sterol, such as cholesterol [37].

Combinations of saponins and cholesterols can be used to form unique particles called immunostimulating complexes (ISCOMs) [chapter 23 of ref 33]. ISCOMs typically also include a phospholipid such as phosphatidylethanolamine or phosphatidylcholine. Any known saponin can be used in ISCOMs. Preferably, the ISCOM includes one or more of QuilA, QHA & QHC. ISCOMs are further described in refs. 37-39. Optionally, the ISCOMS may be devoid of additional detergent [40].

A review of the development of saponin based adjuvants can be found in refs. 41 & 42.

D. Virosomes and Virus-Like Particles

Virosomes and virus-like particles (VLPs) can also be used as adjuvants in the invention. These structures generally contain one or more proteins from a virus optionally combined or formulated with a phospholipid. They are generally non-pathogenic, non-replicating and generally do not contain any of the native viral genome. The viral proteins may be recombinantly produced or isolated from whole viruses. These viral proteins suitable for use in virosomes or VLPs include proteins derived from influenza virus (such as HA or NA), Hepatitis B virus (such as core or capsid proteins), Hepatitis E virus, measles virus, Sindbis virus, Rotavirus, Foot-and-Mouth Disease virus, Retrovirus, Norwalk virus, human Papilloma virus, HIV, RNA-phages, Qβ-phage (such as coat proteins), GA-phage, fr-phage, AP205 phage, and Ty (such as retrotransposon Ty protein p1). VLPs are discussed further in refs. 43-48. Virosomes are discussed further in, for example, ref 49

E. Bacterial or Microbial Derivatives

Adjuvants suitable for use in the invention include bacterial or microbial derivatives such as non-toxic derivatives of enterobacterial lipopolysaccharide (LPS), Lipid A derivatives, immunostimulatory oligonucleotides and ADP-ribosylating toxins and detoxified derivatives thereof.

Non-toxic derivatives of LPS include monophosphoryl lipid A (MPL) and 3-O-deacylated MPL (3dMPL). 3dMPL is a mixture of 3 de-O-acylated monophosphoryl lipid A with 4, 5 or 6 acylated chains. A preferred “small particle” form of 3 De-O-acylated monophosphoryl lipid A is disclosed in ref. 50. Such “small particles” of 3dMPL are small enough to be sterile filtered through a 0.22 μm membrane [50]. Other non-toxic LPS derivatives include monophosphoryl lipid A mimics, such as aminoalkyl glucosaminide phosphate derivatives e.g. RC-529 [51,52].

Lipid A derivatives include derivatives of lipid A from Escherichia coli such as OM-174. OM-174 is described for example in refs. 53 & 54.

Immunostimulatory oligonucleotides suitable for use as adjuvants in the invention include nucleotide sequences containing a CpG motif (a dinucleotide sequence containing an unmethylated cytosine linked by a phosphate bond to a guanosine). Double-stranded RNAs and oligonucleotides containing palindromic or poly(dG) sequences have also been shown to be immunostimulatory.

The CpG's can include nucleotide modifications/analogs such as phosphorothioate modifications and can be double-stranded or single-stranded. References 55, 56 and 57 disclose possible analog substitutions e.g. replacement of guanosine with 2′-deoxy-7-deazaguanosine. The adjuvant effect of CpG oligonucleotides is further discussed in refs. 58-63.

The CpG sequence may be directed to TLR9, such as the motif GTCGTT or TTCGTT [64]. The CpG sequence may be specific for inducing a Th1 immune response, such as a CpG-A ODN, or it may be more specific for inducing a B cell response, such a CpG-B ODN. CpG-A and CpG-B ODNs are discussed in refs. 65-67. Preferably, the CpG is a CpG-A ODN.

Preferably, the CpG oligonucleotide is constructed so that the 5′ end is accessible for receptor recognition. Optionally, two CpG oligonucleotide sequences may be attached at their 3′ ends to form “immunomers”. See, for example, refs. 64 & 68-70.

Bacterial ADP-ribosylating toxins and detoxified derivatives thereof may be used as adjuvants in the invention. Preferably, the protein is derived from E. coli (E. coli heat labile enterotoxin “LT”), cholera (“CT”), or pertussis (“PT”). The use of detoxified ADP-ribosylating toxins as mucosal adjuvants is described in ref. 71 and as parenteral adjuvants in ref. 72. The toxin or toxoid is preferably in the form of a holotoxin, comprising both A and B subunits. Preferably, the A subunit contains a detoxifying mutation; preferably the B subunit is not mutated. Preferably, the adjuvant is a detoxified LT mutant such as LT-K63, LT-R72, and LT-G192. The use of ADP-ribosylating toxins and detoxified derivatives thereof, particularly LT-K63 and LT-R72, as adjuvants can be found in refs. 73-80. Numerical reference for amino acid substitutions is preferably based on the alignments of the A and B subunits of ADP-ribosylating toxins set forth in ref. 81, specifically incorporated herein by reference in its entirety.

F. Human Immunomodulators

Human immunomodulators suitable for use as adjuvants in the invention include cytokines, such as interleukins (e.g. IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12 [82], etc.) [83], interferons (e.g. interferon-γ), macrophage colony stimulating factor, and tumor necrosis factor.

G. Bioadhesives and Mucoadhesives

Bioadhesives and mucoadhesives may also be used as adjuvants in the invention. Suitable bioadhesives include esterified hyaluronic acid microspheres [84] or mucoadhesives such as cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinyl pyrollidone, polysaccharides and carboxymethylcellulose. Chitosan and derivatives thereof may also be used as adjuvants in the invention [85].

H. Microparticles

Microparticles may also be used as adjuvants in the invention. Microparticles (i.e. a particle of ˜100 nm to ˜150 μm in diameter, more preferably ˜200 nm to ˜30 μm in diameter, and most preferably ˜500 nm to ˜10 μm in diameter) formed from materials that are biodegradable and non-toxic (e.g. a poly(α-hydroxy acid), a polyhydroxybutyric acid, a polyorthoester, a polyanhydride, a polycaprolactone, etc.), with poly(lactide-co-glycolide) are preferred, optionally treated to have a negatively-charged surface (e.g. with SDS) or a positively-charged surface (e.g. with a cationic detergent, such as CTAB).

I. Liposomes (Chapters 13 & 14 of ref 33)

Examples of liposome formulations suitable for use as adjuvants are described in refs. 86-88.

J. Polyoxyethylene Ether and Polyoxyethylene Ester Formulations

Adjuvants suitable for use in the invention include polyoxyethylene ethers and polyoxyethylene esters [89]. Such formulations further include polyoxyethylene sorbitan ester surfactants in combination with an octoxynol [90] as well as polyoxyethylene alkyl ethers or ester surfactants in combination with at least one additional non-ionic surfactant such as an octoxynol [91]. Preferred polyoxyethylene ethers are selected from the following group: polyoxyethylene-9-lauryl ether (laureth 9), polyoxyethylene-9-steoryl ether, polyoxytheylene-8-steoryl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether, and polyoxyethylene-23-lauryl ether.

K Polyphosphazene (PCPP)

PCPP formulations are described, for example, in refs. 92 and 93.

L. Muramyl Peptides

Examples of muramyl peptides suitable for use as adjuvants in the invention include N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanyl-D-isoglutamine (nor-MDP), and N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1′-2′-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine MTP-PE).

M. Imidazoquinolone Compounds.

Examples of imidazoquinolone compounds suitable for use adjuvants in the invention include Imiquamod and its homologues (e.g. “Resiquimod 3M”), described further in refs. 94 and 95.

The invention may also comprise combinations of aspects of one or more of the adjuvants identified above. For example, the following adjuvant compositions may be used in the invention: (1) a saponin and an oil-in-water emulsion [96]; (2) a saponin (e.g. QS21)+a non-toxic LPS derivative (e.g. 3dMPL) [97]; (3) a saponin (e.g. QS21)+a non-toxic LPS derivative (e.g. 3dMPL)+a cholesterol; (4) a saponin (e.g. QS21)+3dMPL+IL-12 (optionally+a sterol) [98]; (5) combinations of 3dMPL with, for example, QS21 and/or oil-in-water emulsions [99]; (6) SAF, containing 10% squalane, 0.4% Tween 80™, 5% pluronic-block polymer L121, and thr-MDP, either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion. (7) Ribi™ adjuvant system (RAS), (Ribi Immunochem) containing 2% squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphorylipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), preferably MPL+CWS (Detox™); and (8) one or more mineral salts (such as an aluminum salt)+a non-toxic derivative of LPS (such as 3dMPL).

Other substances that act as immunostimulating agents are disclosed in chapter 7 of ref. 33.

The use of an aluminium hydroxide or aluminium phosphate adjuvant is particularly preferred, and antigens are generally adsorbed to these salts. Calcium phosphate is another preferred adjuvant.

The pH of compositions of the invention is preferably between 6 and 8, preferably about 7. Stable pH may be maintained by the use of a buffer. Where a composition comprises an aluminium hydroxide salt, it is preferred to use a histidine buffer [100]. The composition may be sterile and/or pyrogen-free. Compositions of the invention may be isotonic with respect to humans.

Compositions may be presented in vials, or they may be presented in ready-filled syringes. The syringes may be supplied with or without needles. A syringe will include a single dose of the composition, whereas a vial may include a single dose or multiple doses. Injectable compositions will usually be liquid solutions or suspensions. Alternatively, they may be presented in solid form (e.g. freeze-dried) for solution or suspension in liquid vehicles prior to injection.

Compositions of the invention may be packaged in unit dose form or in multiple dose form. For multiple dose forms, vials are preferred to pre-filled syringes. Effective dosage volumes can be routinely established, but a typical human dose of the composition for injection has a volume of 0.5 ml.

Where a composition of the invention is to be prepared extemporaneously prior to use (e.g. where a component is presented in lyophilised form) and is presented as a kit, the kit may comprise two vials, or it may comprise one ready-filled syringe and one vial, with the contents of the syringe being used to reactivate the contents of the vial prior to injection.

Immunogenic compositions used as vaccines comprise an immunologically effective amount of antigen(s), as well as any other components, as needed. By ‘immunologically effective amount’, it is meant that the administration of that amount to an individual, either in a single dose or as part of a series, is effective for treatment or prevention. This amount varies depending upon the health and physical condition of the individual to be treated, age, the taxonomic group of individual to be treated (e.g. non-human primate, primate, etc.), the capacity of the individual's immune system to synthesise antibodies, the degree of protection desired, the formulation of the vaccine, the treating doctor's assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials, and a typical quantity of each meningococcal saccharide antigen per dose is between 1 μg and 10 mg per antigen.

Pharmaceutical Uses

The invention also provides a method of treating a patient, comprising administering to the patient a therapeutically effective amount of a composition of the invention. The patient may either be at risk from the disease themselves or may be a pregnant woman (‘maternal immunisation’).

The invention provides nucleic acid, polypeptide, or antibody of the invention for use as medicaments (e.g. as immunogenic compositions or as vaccines) or as diagnostic reagents. It also provides the use of nucleic acid, polypeptide, or antibody of the invention in the manufacture of: (i) a medicament for treating or preventing disease and/or infection caused by H. influenzae; (ii) a diagnostic reagent for detecting the presence of H. influenzae or of antibodies raised against H. influenzae; and/or (iii) a reagent which can raise antibodies against H. influenzae. Said H. influenzae serotype or strain, but is preferably a non-typeable H. influenzae. Said disease may be, for instance, otitis media (including acute otitis media), bronchitis, conjunctivitis, sinusitis, a urinary tract infection, pneumonia, bacteremia, septic arthritis, epiglottitis, pneumonia, empyema, pericarditis, cellulitis, osteomyelitis, lower respiratory tract infection or meningitis. The invention is particularly useful for preventing inflammation of the middle ear, by eliciting an immune response that prevents bacteria from moving from the throat to the middle ear via the eustachian tube, where the middle ear is then colonised.

The patient is preferably a human. Where the vaccine is for prophylactic use, the human is preferably a child (e.g. a toddler or infant); where the vaccine is for therapeutic use, the human is preferably an adult. A vaccine intended for children may also be administered to adults e.g. to assess safety, dosage, immunogenicity, etc.

One way of checking efficacy of therapeutic treatment involves monitoring NTHi infection after administration of the composition of the invention. One way of checking efficacy of prophylactic treatment involves monitoring immune responses against an administered polypeptide after administration. Immunogenicity of compositions of the invention can be determined by administering them to test subjects (e.g. children 12-16 months age, or animal models [e.g. a chinchilla model [146]) and then determining standard parameters including ELISA titres (GMT) of IgG. These immune responses will generally be determined around 4 weeks after administration of the composition, and compared to values determined before administration of the composition.

Where more than one dose of the composition is administered, more than one post-administration determination may be made.

Administration of polypeptide antigens is a preferred method of treatment for inducing immunity. Administration of antibodies of the invention is another preferred method of treatment. This method of passive immunisation is particularly useful for newborn children or for pregnant women. This method will typically use monoclonal antibodies, which will be humanised or fully human.

Compositions of the invention will generally be administered directly to a patient. Direct delivery may be accomplished by parenteral injection (e.g. subcutaneously, intraperitoneally, intravenously, intramuscularly, or to the interstitial space of a tissue), or by rectal, oral, vaginal, topical, transdermal, intranasal, ocular, aural, pulmonary or other mucosal administration. Intramuscular administration to the thigh or the upper arm is preferred. Injection may be via a needle (e.g. a hypodermic needle), but needle-free injection may alternatively be used. A typical intramuscular dose is 0.5 ml.

The invention may be used to elicit systemic and/or mucosal immunity.

Dosage treatment can be a single dose schedule or a multiple dose schedule. Multiple doses may be used in a primary immunisation schedule and/or in a booster immunisation schedule. A primary dose schedule may be followed by a booster dose schedule. Suitable timing between priming doses (e.g. between 4-16 weeks), and between priming and boosting, can be routinely determined.

Bacterial infections affect various areas of the body and so compositions may be prepared in various forms. For example, the compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared (e.g. a lyophilised composition). The composition may be prepared for topical administration e.g. as an ointment, cream or powder. The composition be prepared for oral administration e.g. as a tablet or capsule, or as a syrup (optionally flavoured). The composition may be prepared for pulmonary administration e.g. as an inhaler, using a fine powder or a spray. The composition may be prepared as a suppository or pessary. The composition may be prepared for nasal, aural or ocular administration e.g. as spray, drops, gel or powder [e.g. refs 101 & 102].

Combinations

Within the >2500 proteins described in the examples, NTH0861, NTH0863, NTH0865 and NTH0867 are particularly preferred for use with the invention (particularly in vaccines), and these four proteins can be used in combinations. Thus the invention provides a composition comprising: (a) a NTH0861 protein; and (b) at least one further NTHi protein. The invention also provides a composition comprising: (a) a NTH0863 protein; and (b) at least one further NTHi protein. The invention also provides a composition comprising: (a) a NTH0865 protein; and (b) at least one further NTHi protein. The invention also provides a composition comprising: (a) a NTH0867 protein; and (b) at least one further NTHi protein. The further NTHi protein can be selected from proteins of the invention as described above.

The combinations are preferably selected within these four proteins, and so the invention provides a composition comprising two or more (i.e. 2, 3 or 4) of NTH0861, NTH0863, NTH0865 and/or NTH0867. Preferred compositions comprise: (1) NTH0861 and NTH0863; (2) NTH0861 and NTH0865; (3) NTH0861 and NTH0867; (4) NTH0863 and NTH0865; (5) NTH0863 and NTH0867; (6) NTH0865 and NTH0867; (7) NTH0861, NTH0863 and NTH0865; (8) NTH0861, NTH0863 and NTH0867; (9) NTH0863, NTH0865 and NTH0867; (10) NTH0861, NTH0865 and NTH0867; (11) NTH0861, NTH0863, NTH0865 and NTH0867.

The NTH0861 protein preferably comprises SEQ ID NO: 1566, SEQ ID NO: 5095, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1566 and/or to SEQ ID NO: 5095. The NTH0863 protein preferably comprises SEQ ID NO: 1570, SEQ ID NO: 5094, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1570 and/or to SEQ ID NO: 5094. The NTH0865 protein preferably comprises SEQ ID NO: 1574, SEQ ID NO: 5093, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1574 and/or to SEQ ID NO: 5093. The NTH0867 protein preferably comprises SEQ ID NO: 1578, SEQ ID NO: 5092, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1578 and/or to SEQ ID NO: 5092.

Further Antigenic Components of Compositions of the Invention

The invention also provides a composition comprising a polypeptide or the invention and one or more of the following further antigens:

-   -   a saccharide antigen from N. meningitidis serogroup A, C, W135         and/or Y (preferably all four), such as the oligosaccharide         disclosed in ref. 103 from serogroup C [see also ref. 104] or         the oligosaccharides of ref. 105.     -   a saccharide antigen from Streptococcus pneumoniae [e.g. 106,         107, 108].     -   an antigen from hepatitis A virus, such as inactivated virus         [e.g. 109, 110].     -   an antigen from hepatitis B virus, such as the surface and/or         core antigens [e.g. 110, 111].     -   a diphtheria antigen, such as a diphtheria toxoid [e.g. chapter         3 of ref. 112] e.g. the CRM₁₉₇ mutant [e.g. 113].     -   a tetanus antigen, such as a tetanus toxoid [e.g. chapter 4 of         ref. 112].     -   an antigen from Bordetella pertussis, such as pertussis         holotoxin (PT) and filamentous haemagglutinin (FHA) from B.         pertussis, optionally also in combination with pertactin and/or         agglutinogens 2 and 3 [e.g. refs. 114 & 115].     -   a saccharide antigen from Haemophilus influenzae B [e.g. 104].     -   polio antigen(s) [e.g. 116, 117] such as IPV.     -   measles, mumps and/or rubella antigens [e.g. chapters 9, 10 & 11         of ref. 112].     -   influenza antigen(s) [e.g. chapter 19 of ref. 112], such as the         haemagglutinin and/or neuraminidase surface proteins.     -   an antigen from Moraxella catarrhalis [e.g. 118].     -   an protein antigen from Streptococcus agalactiae (group B         streptococcus) [e.g. 119, 120].     -   a saccharide antigen from Streptococcus agalactiae (group B         streptococcus).     -   an antigen from Streptococcus pyogenes (group A streptococcus)         [e.g. 120, 121, 122].     -   an antigen from Staphylococcus aureus [e.g. 123].

The composition may comprise one or more of these further antigens.

Toxic protein antigens may be detoxified where necessary (e.g. detoxification of pertussis toxin by chemical and/or genetic means [115]).

Where a diphtheria antigen is included in the composition it is preferred also to include tetanus antigen and pertussis antigens. Similarly, where a tetanus antigen is included it is preferred also to include diphtheria and pertussis antigens. Similarly, where a pertussis antigen is included it is preferred also to include diphtheria and tetanus antigens. DTP combinations are thus preferred.

Saccharide antigens are preferably in the form of conjugates. Carrier proteins for the conjugates include diphtheria toxin, tetanus toxin, the N. meningitidis outer membrane protein [124], synthetic peptides [125,126], heat shock proteins [127,128], pertussis proteins [129,130], protein D from H. influenzae [131], cytokines [132], lymphokines [132], streptococcal proteins, hormones [132], growth factors [132], toxin A or B from C. difficile [133], iron-uptake proteins [134], etc. A preferred carrier protein is the CRM197 diphtheria toxoid [135].

Antigens in the composition will typically be present at a concentration of at least 1 μg/ml each. In general, the concentration of any given antigen will be sufficient to elicit an immune response against that antigen.

As an alternative to using proteins antigens in the immunogenic compositions of the invention, nucleic acid (preferably DNA e.g. in the form of a plasmid) encoding the antigen may be used.

Antigens are preferably adsorbed to an aluminium salt.

Screening Methods

The invention provides a process for determining whether a test compound binds to a polypeptide of the invention. If a test compound binds to a polypeptide of the invention and this binding inhibits the life cycle of the H. influenzae bacterium, then the test compound can be used as an antibiotic or as a lead compound for the design of antibiotics. The process will typically comprise the steps of contacting a test compound with a polypeptide of the invention, and determining whether the test compound binds to said polypeptide. Preferred polypeptides of the invention for use in these processes are enzymes (e.g. tRNA synthetases), membrane transporters and ribosomal polypeptides. Suitable test compounds include polypeptides, polypeptides, carbohydrates, lipids, nucleic acids (e.g. DNA, RNA, and modified forms thereof), as well as small organic compounds (e.g. MW between 200 and 2000 Da). The test compounds may be provided individually, but will typically be part of a library (e.g. a combinatorial library). Methods for detecting a binding interaction include NMR, filter-binding assays, gel-retardation assays, displacement assays, surface plasmon resonance, reverse two-hybrid etc. A compound which binds to a polypeptide of the invention can be tested for antibiotic activity by contacting the compound with GBS bacteria and then monitoring for inhibition of growth. The invention also provides a compound identified using these methods.

Preferably, the process comprises the steps of: (a) contacting a polypeptide of the invention with one or more candidate compounds to give a mixture; (b) incubating the mixture to allow polypeptide and the candidate compound(s) to interact; and (c) assessing whether the candidate compound binds to the polypeptide or modulates its activity.

Once a candidate compound has been identified in vitro as a compound that binds to a polypeptide of the invention then it may be desirable to perform further experiments to confirm the in vivo function of the compound in inhibiting bacterial growth and/or survival. Thus the method comprise the further step of contacting the compound with a NTHi bacterium and assessing its effect.

The polypeptide used in the screening process may be free in solution, affixed to a solid support, located on a cell surface or located intracellularly. Preferably, the binding of a candidate compound to the polypeptide is detected by means of a label directly or indirectly associated with the candidate compound. The label may be a fluorophore, radioisotope, or other detectable label.

General

The invention provides a computer-readable medium (e.g. a floppy disk, a hard disk, a CD-ROM, a DVD etc.) and/or a computer memory and/or a computer database containing one or more of the sequences in the sequence listing.

The term “comprising” encompasses “including” as well as “consisting” e.g. a composition “comprising” X may consist exclusively of X or may include something additional e.g. X+Y.

The term “about” in relation to a numerical value x means, for example, x±10%.

The word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.

The N-terminus residues in the amino acid sequences in the sequence listing are given as the amino acid encoded by the first codon in the corresponding nucleotide sequence. Where the first codon is not ATG, it will be understood that it will be translated as methionine when the codon is a start codon, but will be translated as the indicated non-Met amino acid when the sequence is at the C-terminus of a fusion partner. The invention specifically discloses and encompasses each of the amino acid sequences of the sequence listing having a N-terminus methionine residue (e.g. a formyl-methionine residue) in place of any indicated non-Met residue.

Alternative start codons can be used in biology. The amino acid sequences in the sequence listing are based on particular start codons, but downstream start codons may alternatively be used. Thus the invention specifically discloses and encompasses each of the amino acid sequences of the sequence listing, starting at any methionine residue from the sequence that is downstream of the N-terminal residue shown in the sequence listing (e.g. SEQ ID NOS: 5088, 5089 & 5090).

As indicated in the above text, nucleic acids and polypeptides of the invention may include sequences that:

-   -   (a) are identical (i.e. 100% identical) to the sequences         disclosed in the sequence listing;     -   (b) share sequence identity with the sequences disclosed in the         sequence listing;     -   (c) have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 single nucleotide or         amino acid alterations (deletions, insertions, substitutions),         which may be at separate locations or may be contiguous, as         compared to the sequences of (a) or (b); and     -   (d) when aligned with a particular sequence from the sequence         listing using a pairwise alignment algorithm, a moving window of         x monomers (amino acids or nucleotides) moving from start         (N-terminus or 5′) to end (C-terminus of 3′), such that for an         alignment that extends to p monomers (where p>x) there are p-x+l         such windows, each window has at least xy identical aligned         monomers, where: x is selected from 20, 25, 30, 35, 40, 45, 50,         60, 70, 80, 90, 100, 150, 200; y is selected from 0.50, 0.60,         0.70, 0.75, 0.80, 0.85, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95,         0.96, 0.97, 0.98, 0.99; and if xy is not an integer then it is         rounded up to the nearest integer. The preferred pairwise         alignment algorithm is the Needleman-Wunsch global alignment         algorithm [136], using default parameters (e.g. with Gap opening         penalty=10.0, and with Gap extension penalty=0.5, using the         EBLOSUM62 scoring matrix). This algorithm is conveniently         implemented in the needle tool in the EMBOSS package [137].

The nucleic acids and polypeptides of the invention may additionally have further sequences to the N-terminus/5′ and/or C-terminus/3′ of these sequences (a) to (d).

The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., references 138-145, etc.

MODES FOR CARRYING OUT THE INVENTION

Genome sequencing has been carried out on a low-passage clinical NTHi isolate (strain 86-028NP [146]). A total of 2540 coding sequences were identified in the genome, and these are given in the sequence listing together with their inferred translation products. Annotation of 1489 of the polypeptide sequences is given in Table III. From the sequenced material, polypeptide-coding sequences of particular interest were selected for further work, with particular attention to immunogenic proteins for vaccine development.

Lipoproteins

Of the 2540 coding sequences, the following 39 were identified as lipoproteins: NTH0094, NTH10163, NTH0167, NTH0255, NTH0289, NTH-0838, NTH-0909, NTH0997, NTH1000, NTH1016, NTH11174, NTH1298, NTH1313, NIH1413, NIH1416, NTH1552, NTH1623, NIH1675, NIH1680, NTH1739, NTH1873, NTH1922, NTH1942, NIH1974, NTH2142, NTH2169, NTH2251, NTH2349, NTH2356, NTH2358, NTH2524, NTH2588, NTH2595, NTH2641, NTH2673, NTH2715, NIH2754, NTH2758, and NTH2769. Lipoproteins are surface-exposed and, as such, they represent accessible immunological targets e.g. for diagnostic and for immunisation purposes. Moreover, it has been found in B. burgdorferi [147] that OspA protein is immunogenic in a lipidated form but is non-immunogenic in a non-lipidated form, and the authors concluded that post-translational lipid attachment is a critical determinant of OspA immunogenicity.

Outer Membrane

As H. influenzae is a Gram-negative bacterium, its cell wall includes an outer membrane. Of the 2540 coding sequences, the following 48 were identified as being located in this outer membrane: NTH0017, NTH0193, NTH0227, NTH0241, NTH0252, NTH0270, NTH0432, NTH0498, NTH0502, NTH0504, NTH0512, NTH0539, NTH0638, NTH0647, NTH0648, NTH0788, NTH0839, NTH0867, NTH0914, NTH1054, NTH1075, NTH1082, NTH1200, NTH1203, NTH1214, NTH1290, NTH1390, NTH1582, NTH1652, NTH1666, NTH1744, NTH1819, NTH1845, NTH1900, NTH1953, NTH1956, NTH1958, NTH1962, NTH2039, NTH2232, NTH2234, NTH2235, NTH2269, NTH2448, NTH2484, NTH2493, and NTH2727. Outer membrane proteins (OMPs) are surface-exposed and, as such, they represent accessible immunological targets e.g. for diagnostic and for immunisation purposes. OMPs are often invasins, adhesins, etc. which, if blocked, offers a means of preventing bacterial infection.

NTH1845 is an Aida-like autotransporter (‘Lav’) and is a preferred protein of the invention. It is conserved between NTHi strains, including one known to cause meningitis, but there is no corresponding gene in the Rd sequence or in strain R2846. It lies between the tmk and holb genes. A preferred form of NTH1845 starts at Met-22 (i.e. SEQ ID NO: 5090).

Periplasm

As H. influenzae is a Gram-negative bacterium, it has a periplasm between its cell cytoplasmic membrane and its outer membrane. Of the 2540 coding sequences, the following 105 were identified as being located in the periplasm: NTH0014, NTH1049, NTH0057, NTH0059, NTH0106, NTH0119, NTH0120, NTH0132, NTH0174, NTH0190, NTH0206, NTH0244, NTH0346, NTH0405, NTH0421, NTH0468, NTH0485, NTH0513, NTH0547, NTH0619, NTH0643, NTH0661, NTH0691, NTH0738, NTH0820, NTH0835, NTH0848, NTH0849, NTH0856, NTH0861, NTH0863, NTH0865, NTH0910, NTH0926, NTH0961, NTH1015, NTH1018, NTH1121, NTH1164, NTH1185, NTH1190, NTH1261, NTH1268, NTH1301, NTH1311, NTH1388, NTH1394, NTH1406, NTH1407, NTH1414, NTH1435, NTH1468, NTH1541, NTH1570, NTH1600, NTH1601, NTH1619, NTH1622, NTH1724, NTH1745, NTH1773, NTH1781, NTH1798, NTH1807, NTH1829, NTH1865, NTH1871, NTH1892, NTH1897, NTH1916, NTH1917, NTH1965, NTH1999, NTH2116, NTH2119, NTH2133, NTH2135, NTH2149, NTH2150, NTH2187, NTH2217, NTH2227, NTH2256, NTH2258, NTH2277, NTH2291, NTH2316, NTH2342, NTH2344, NTH2369, NTH2394, NTH2432, NTH2434, NTH2451, NTH2496, NTH2508, NTH2537, NTH2541, NTH2572, NTH2575, NTH2610, NTH2705, NTH2726, NTH2738, and NTH2778. Periplasmic proteins represent useful immunological targets e.g. for diagnostic and for immunisation purposes.

Inner Membrane

As H. influenzae is a Gram-negative bacterium, it has an inner membrane. Of the 2540 coding sequences, the following 740 were identified as being located in the inner membrane: NTH0002, NTH0015, NTH0019, NTH0020, NTH0021, NTH0025, NTH0032, NTH0034, NTH0035, NTH0041, NTH0043, NTH0045, NTH0048, NTH0050, NTH0052, NTH0060, NTH0061, NTH0067, NTH0073, NTH0076, NTH0085, NTH0089, NTH0091, NTH0097, NTH0107, NTH0110, NTH0116, NTH0118, NTH0121, NTH0128, NTH0134, NTH0135, NTH0151, NTH0155, NTH0157, NTH0158, NTH0180, NTH0184, NTH0185, NTH0186, NTH0189, NTH0199, NTH0203, NTH0208, NTH0209, NTH0223, NTH0224, NTH0228, NTH0232, NTH0237, NTH0238, NTH0242, NTH0247, NTH0248, NTH0251, NTH0253, NTH0254, NTH0256, NTH0263, NTH0269, NTH0278, NTH0279, NTH0280, NTH0290, NTH0295, NTH0297, NTH0302, NTH0307, NTH0311, NTH0317, NTH0320, NTH0321, NTH0325, NTH0326, NTH0333, NTH0334, NTH0341, NTH0347, NTH0351, NTH0352, NTH0353, NTH0356, NTH0358, NTH0366, NTH0371, NTH0372, NTH0388, NTH0397, NTH0400, NTH0401, NTH0402, NTH0407, NTH0411, NTH0412, NTH0417, NTH0418, NTH0420, NTH0426, NTH0427, NTH0434, NTH0435, NTH0437, NTH0444, NTH0453, NTH0455, NTH0457, NTH0459, NTH0460, NTH0461, NTH0462, NTH0463, NTH0465, NTH0469, NTH0473, NTH0475, NTH0478, NTH0484, NTH0489, NTH0490, NTH0493, NTH0496, NTH0507, NTH0509, NTH0518, NTH0524, NTH0526, NTH0528, NTH0529, NTH0544, NTH0545, NTH0549, NTH0565, NTH0566, NTH0574, NTH0580, NTH0581, NTH0584, NTH0585, NTH0586, NTH0587, NTH0590, NTH0617, NTH0618, NTH0622, NTH0624, NT10626, NTH0630, NTH0636, NTH0637, NTH0642, NTH0644, NTH0646, NTH0654, NTH0656, NTH0658, NTH0673, NTH0675, NTH0676, NTH0677, NTH0678, NTH0680, NTH01694, NTH0696, NTH0702, NTH0703, NTH0706, NTH0709, NTH0710, NTH0712, NTH0715, NTH0718, NTH0728, NTH0730, NTH0740, NTH0744, NTH0745, NTH0749, NTH0750, NTH0755, NTH0762, NTH0764, NTH0765, NTH0771, NTH0774, NTH0794, NTH0795, NTH0796, NTH0797, NTH0798, NTH0802, NTH0803, NTH0804, NTH0813, NTH0814, NTH0815, NTH0821, NTH0822, NTH0827, NTH0829, NTH0834, NTH0836, NTH850, NTH0851, NTH0852, NTH0858, NTH0872, NTH0874, NTH0875, NTH0880, NTH0887, NTH0888, NTH0894, NTH0904, NTH0913, NTH0927, NTH0928, NTH0941, NTH0948, NTH0949, NTH0950, NTH0952, NTH0953, NTH0955, NTH0964, NTH0968, NTH0973, NTH0986, NTH0987, NTH0989, NTH0994, NTH0996, NTH1002, NTH1003, NTH1004, NTH1005, NTH1009, NTH1010, NTH1012, NTH1020, NTH1021, NTH1026, NTH1028, NTH1031, NTH1032, NTH1037, NTH1039, NTH1042, NTH1043, NTH1048, NTH1052, NTH1058, NTH1063, NTH1064, NTH1069, NTH1073, NTH1080, NTH1083, NTH1084, NTH1085, NTH1086, NTH1087, NTH1089, NTH1090, NTH1091, NTH1092, NTH1098, NTH1102, NTH1103, NTH1104, NTH1106, NTH1123, NTH1124, NTH1125, NTH1130, NTH1138, NTH1141, NTH1150, NTH1151, NTH1178, NTH1181, NTH1184, NTH1188, NTH1189, NTH1191, NTH1192, NTH1193, NTH1201, NTH1205, NTH1216, NTH1220, NTH1221, NTH1224, NTH1225, NTH1226, NTH1229, NTH1230, NTH1231, NTH1233, NTH1234, NTH1236, NTH1238, NTH1240, NTH1241, NTH1250, NTH1252, NTH1254, NTH1255, NTH1256, NTH1262, NTH1273, NTH1275, NTH1279, NTH1280, NTH1281, NTH1282, NTH1283, NTH1286, NTH1287, NTH1293, NTH1295, NTH1297, NTH1300, NTH1302, NTH1305, NTH1306, NTH1307, NTH1308, NTH1309, NTH1315, NTH1319, NTH1321, NTH1327, NTH1332, NTH1334, NTH1336, NTH1337, NTH1341, NTH1346, NTH1348, NTH1354, NTH1357, NTH1359, NTH1363, NTH1365, NTH1368, NTH1374, NTH1376, NTH1379, NTH1380, NTH1383, NTH1391, NTH1393, NTH1398, NTH1400, NTH1411, NTH1412, NTH1420, NTH1421, NTH1425, NTH1427, NTH1428, NTH1429, NTH1430, NTH1431, NTH1434, NTH1437, NTH1438, NTH1439, NTH1447, NTH1448, NTH1450, NTH1454, NTH1455, NTH1464, NTH1467, NTH1470, NTH1471, NTH1472, NTH1473, NTH1474, NTH1479, NTH1491, NTH1492, NTH1493, NTH1495, NTH1500, NTH1503, NTH1506, NTH1510, NTH1515, NTH1525, NTH1526, NTH1527, NTH1528, NTH1531, NTH1532, NTH1537, NTH1538, NTH1540, NTH1548, NTH1559, NTH1562, NTH1567, NTH1569, NTH1573, NTH1575, NTH1581, NTH1584, NTH1586, NTH1587, NTH1588, NTH1590, NTH1594, NTH1597, NTH1599, NTH1602, NTH1605, NTH1606, NTH1608, NTH1609, NTH1617, NTH1618, NTH1620, NTH1621, NTH1625, NTH1629, NTH1631, NTH1634, NTH1637, NTH1638, NTH1653, NTH1654, NTH1657, NTH1662, NTH1664, NTH1668, NTH1671, NTH1686, NTH1687, NTH1688, NTH1689, NTH1690, NTH1692, NTH1693, NTH1698, NTH1701, NTH1707, NTH1712, NTH1718, NTH1719, NTH1722, NTH1725, NTH1729, NTH1732, NTH1735, NTH1760, NTH1767, NTH1770, NTH1778, NTH1779, NTH1782, NTH1783, NTH1788, NTH1793, NTH1795, NTH1796, NTH1799, NTH1803, NTH1805, NTH1806, NTH1813, NTH1815, NTH1820, NTH1824, NTH1828, NTH1835, NTH1836, NTH1842, NTH1849, NTH1850, NTH1859, NTH1861, NTH1870, NTH1872, NTH1881, NTH1882, NTH1885, NTH1888, NTH1889, NTH1891, NTH1896, NTH1898, NTH1899, NTH1906, NTH1908, NTH1919, NTH1923, NTH1925, NTH1927, NTH1935, NTH1939, NTH1941, NTH1951, NTH1960, NTH1963, NTH1966, NTH1967, NTH1968, NTH1978, NTH1981, NTH1986, NTH1992, NTH1993, NTH1995, NTH1996, NTH1997, NTH1998, NTH2001, NTH2005, NTH2008, NTH2009, NTH2010, NTH2024, NTH2025, NTH2038, NTH2040, NTH2041, NTH2043, NTH2050, NTH2052, NTH2055, NTH2060, NTH2062, NTH2064, NTH2065, NTH2070, NTH2071, NTH2073, NTH2078, NTH2079, NTH2081, NTH2083, NTH2089, NTH2091, NTH2092, NTH2093, NTH2094, NTH2095, NTH2096, NTH2097, NTH2099, NTH2101, NTH2112, NTH2115, NTH2118, NTH2120, NTH2122, NTH2126, NTH2128, NTH2129, NTH2130, NTH2131, NTH2136, NTH2138, NTH2145, NTH2146, NTH2162, NTH2163, NTH2166, NTH2169, NTH2170, NTH2173, NTH2181, NTH2183, NTH2191, NTH2193, NTH2195, NTH2196, NTH2200, NTH2204, NTH2205, NTH2209, NTH2213, NTH2226, NTH2228, NTH2231, NTH2242, NTH2243, NTH2247, NTH2250, NTH2253, NTH2257, NTH2259, NTH2262, NTH2263, NTH2266, NTH2273, NTH2274, NTH2282, NTH2284, NTH2285, NTH2288, NTH2292, NTH2296, NTH2299, NTH2318, NTH2323, NTH2324, NTH2326, NTH2327, NTH2333, NTH2343, NTH2346, NTH2347, NTH2352, NTH2361, NTH2364, NTH2365, NTH2368, NTH2370, NTH2371, NTH2376, NTH2377, NTH2381, NTH2382, NTH2388, NTH2398, NTH2402, NTH2405, NTH2406, NTH2407, NTH2408, NTH2414, NTH2422, NTH2430, NTH2433, NTH2438, NTH2447, NTH2455, NTH2457, NTH2458, NTH2472, NTH2478, NTH2481, NTH2486, NTH2495, NTH2497, NTH2498, NTH2499, NTH2501, NTH2505, NTH2525, NTH2531, NTH2532, NTH2533, NTH2534, NTH2542, NTH2543, NTH2545, NTH2546, NTH2548, NTH2549, NTH2550, NTH2552, NTH2554, NTH2556, NTH2557, NTH2558, NTH2562, NTH2566, NTH2567, NTH2568, NTH2569, NTH2570, NTH2573, NTH2577, NTH2578, NTH2587, NTH2591, NTH2593, NTH2597, NTH2600, NTH2602, NTH2603, NTH2604, NTH2605, NTH2612, NTH2613, NTH2615, NTH2616, NTH2618, NTH2626, NTH2633, NTH2640, NTH2647, NTH2648, NTH2649, NTH2650, NTH2661, NTH2663, NTH2664, NTH2667, NTH2668, NTH2674, NTH2675, NTH2680, NTH2690, NTH2701, NTH2702, NTH2703, NTH2708, NTH2711, NTH2724, NTH2725, NTH2732, NTH2735, NTH2740, NTH2743, NTH2749, NTH2750, NTH2755, NTH2756, NTH2757, NTH2764, NTH2765, NTH2774, NTH2777, NTH2779, NTH2781, NTH2793, NTH2794, NTH2796, NTH2797, NTH2798, NTH2806, NTH2807, NTH2813, NTH2814, NTH2823, and NTH2824. Inner membrane proteins represent useful immunological targets e.g. for diagnostic and for immunisation purposes.

Of these proteins, NTH1069 in particular has been identified as a virulence-associated protein. A preferred form of this protein starts at Met-27 (i.e. SEQ ID NO: 5088). Another preferred form starts at Met-19 (SEQ ID NO: 5089).

Adhesin

An adhesin having amino acid sequence SEQ ID NO: 5091 has been identified in a NTHi strain isolated from a patient with meningitis. It is homologous to the Hia adhesin from N. meningitidis.

H. influenzae Rd

The genome sequence of the serotype d strain KW20 [1,3] was published in 1995. As serotype d strains are generally not pathogens, but the sequenced NTHi strain is from a clinical infection, expressed NTHi sequences that are not seen in serotype d are likely to be the proteins that are involved in pathogenic mechanisms. Blocking these proteins, either by antibiotic treatment or by antibody binding, thus has therapeutic potential. Of the 2540 coding sequences, the following 613 are not seen in the Rd genome: NTH0001, NTH0002, NTH0004, NTH0005, NTH0012, NTH0016, NTH0021, NTH0022, NTH0024, NTH0032, NTH0033, NTH0034, NTH0035, NTH0036, NTH0037, NTH0038, NTH0040, NTH0045, NTH0050, NTH0051, NTH0052, NTH0053, NTH0064, NTH0089, NTH0092, NTH0097, NTH0101, NTH0104, NTH0110, NTH0114, NTH0122, NTH0123, NTH0124, NTH0125, NTH0129, NTH0135, NTH0136, NTH0138, NTH0140, NTH0146, NTH0148, NTH0151, NTH0153, NTH0154, NTH0159, NTH0161, NTH0164, NTH0169, NTH0173, NTH0176, NTH0177, NTH0187, NTH0191, NTH0192, NTH0193, NTH0194, NTH0195, NTH0197, NTH0198, NTH0199, NTH0226, NTH0235, NTH0236, NTH0238, NTH0250, NTH0251, NTH0254, NTH0255, NTH0256, NTH0264, NTH0265, NTH0278, NTH0279, NTH0280, NTH0282, NTH0283, NTH0284, NTH0285, NTH0289, NTH0297, NTH0298, NTH0299, NTH0300, NTH0302, NTH0307, NTH0308, NTH0312, NTH0313, NTH0319, NTH0327, NTH0328, NTH0331, NTH0334, NTH0335, NTH0339, NTH0341, NTH0348, NTH0363, NTH0371, NTH0375, NTH0378, NTH0379, NTH0384, NTH0385, NTH0396, NTH0407, NTH0408, NTH0411, NTH0417, NTH0419, NTH0420, NTH0424, NTH0429, NTH0430, NTH0431, NTH0432, NTH0433, NTH0434, NTH0435, NTH0438, NTH0455, NTH0478, NTH0484, NTH0485, NTH0486, NTH0487, NTH0488, NTH0489, NTH0498, NTH0500, NTH0501, NTH0506, NTH0509, NTH0510, NTH0511, NTH0520, NTH0523, NTH0526, NTH0527, NTH0531, NTH0534, NTH0536, NTH0539, NTH0559, NTH0561, NTH0573, NTH0577, NTH0579, NTH0580, NTH0581, NTH0582, NTH0583, NTH0584, NTH0585, NTH0586, NTH0588, NTH0599, NTH0603, NTH0604, NTH0606, NTH0615, NTH0617, NTH0631, NTH0637, NTH0644, NTH0645, NTH0653, NTH0662, NTH0663, NTH0664, NTH0667, NTH0668, NTH0673, NTH0677, NTH0680, NTH0681, NTH0683, NTH0687, NTH0690, NTH0691, NTH0692, NTH0694, NTH0695, NTH0696, NTH0706, NTH0707, NTH0711, NTH0715, NTH0716, NTH0717, NTH0721, NTH0724, NTH0725, NTH0726, NTH0728, NTH0729, NTH0730, NTH0749, NTH0752, NTH0756, NTH0768, NTH0776, NTH0792, NTH0797, NTH0818, NTH0827, NTH0832, NTH0839, NTH0841, NTH0843, NTH0844, NTH0862, NTH0864, NTH0866, NTH0867, NTH0877, NTH0879, NTH0885, NTH0886, NTH0892, NTH0895, NTH0896, NTH0900, NTH0901, NTH0904, NTH0906, NTH0921, NTH0924, NTH0928, NTH0929, NTH0930, NTH0931, NTH0932, NTH0933, NTH0937, NTH0938, NTH0942, NTH0949, NTH0953, NTH0955, NTH0961, NTH0964, NTH0970, NTH0971, NTH0972, NTH0973, NTH0985, NTH0987, NTH0991, NTH0992, NTH0993, NTH0994, NTH0995, NTH0996, NTH1007, NTH1016, NTH1017, NTH1020, NTH1025, NTH1026, NTH1027, NTH1028, NTH1029, NTH1037, NTH1040, NTH1049, NTH1067, NTH1069, NTH1070, NTH1073, NTH1082, NTH1086, NTH1089, NTH1090, NTH1108, NTH1111, NTH1112, NTH1114, NTH1115, NTH1116, NTH1122, NTH1129, NTH1131, NTH1142, NTH1149, NTH1150, NTH1153, NTH1157, NTH1159, NTH1161, NTH1162, NTH1176, NTH1178, NTH1179, NTH1193, NTH1195, NTH1196, NTH1204, NTH1205, NTH1207, NTH1208, NTH1209, NTH1210, NTH1211, NTH1214, NTH1216, NTH1220, NTH1225, NTH1234, NTH1235, NTH1237, NTH1241, NTH1244, NTH1245, NTH1246, NTH1247, NTH1248, NTH1249, NTH1250, NTH1251, NTH1252, NTH1253, NTH1270, NTH1271, NTH1294, NTH1299, NTH1313, NTH1315, NTH1316, NTH1325, NTH1330, NTH1333, NTH1337, NTH1339, NTH1342, NTH1353, NTH1361, NTH1367, NTH1374, NTH1375, NTH1381, NTH1382, NTH1390, NTH1391, NTH1395, NTH1396, NTH1399, NTH1414, NTH1415, NTH1418, NTH1419, NTH1437, NTH1441, NTH1454, NTH1456, NTH1471, NTH1474, NTH1487, NTH1489, NTH1490, NTH1491, NTH1492, NTH1493, NTH1494, NTH1495, NTH1496, NTH1497, NTH1504, NTH1516, NTH1540, NTH1543, NTH1555, NTH1563, NTH1564, NTH1567, NTH1571, NTH1573, NTH1574, NTH1580, NTH1587, NTH1598, NTH1599, NTH1600, NTH1601, NTH1602, NTH1603, NTH1605, NTH1606, NTH1607, NTH1611, NTH1612, NTH1615, NTH1616, NTH1626, NTH1627, NTH1628, NTH1647, NTH1656, NTH1657, NTH1658, NTH1676, NTH1677, NTH1687, NTH1697, NTH1702, NTH1703, NTH1713, NTH1734, NTH1740, NTH1742, NTH1744, NTH1745, NTH1748, NTH1749, NTH1751, NTH1752, NTH1753, NTH1754, NTH1755, NTH1756, NTH1757, NTH1758, NTH1759, NTH1760, NTH1765, NTH1769, NTH1770, NTH1778, NTH1798, NTH1804, NTH1811, NTH1812, NTH1815, NTH1816, NTH1817, NTH1818, NTH1820, NTH1821, NTH1822, NTH1829, NTH1832, NTH1833, NTH1837, NTH1842, NTH1845, NTH1854, NTH1857, NTH1904, NTH1910, NTH1914, NTH1916, NTH1920, NTH1921, NTH1922, NTH1945, NTH1946, NTH1947, NTH1948, NTH1956, NTH1962, NTH1964, NTH1968, NTH1989, NTH1994, NTH2019, NTH2031, NTH2035, NTH2043, NTH2056, NTH2060, NTH2069, NTH2075, NTH2093, NTH2096, NTH2109, NTH2110, NTH2112, NTH2113, NTH2114, NTH2117, NTH2156, NTH2159, NTH2170, NTH2197, NTH2198, NTH2199, NTH2206, NTH2207, NTH2216, NTH2217, NTH2219, NTH2220, NTH2221, NTH2222, NTH2223, NTH2226, NTH2229, NTH2245, NTH2273, NTH2284, NTH2287, NTH2305, NTH2309, NTH2315, NTH2316, NTH2323, NTH2326, NTH2330, NTH2332, NTH2343, NTH2349, NTH2353, NTH2362, NTH2363, NTH2364, NTH2386, NTH2414, NTH2442, NTH2451, NTH2455, NTH2456, NTH2457, NTH2458, NTH2460, NTH2461, NTH2463, NTH2464, NTH2466, NTH2467, NTH2468, NTH2471, NTH2480, NTH2481, NTH2482, NTH2483, NTH2484, NTH2485, NTH2486, NTH2487, NTH2488, NTH2500, NTH2510, NTH2524, NTH2525, NTH2527, NTH2528, NTH2536, NTH2537, NTH2549, NTH2562, NTH2563, NTH2572, NTH2573, NTH2575, NTH2584, NTH2585, NTH2590, NTH2604, NTH2607, NTH2608, NTH2609, NTH2635, NTH2647, NTH2648, NTH2650, NTH2655, NTH2664, NTH2668, NTH2679, NTH2684, NTH2693, NTH2694, NTH2696, NTH2697, NTH2703, NTH2704, NTH2706, NTH2707, NTH2708, NTH2709, NTH2710, NTH2711, NTH2712, NTH2713, NTH2715, NTH2716, NTH2718, NTH2719, NTH2720, NTH2721, NTH2723, NTH2724, NTH2725, NTH2726, NTH2727, NTH2729, NTH2730, NTH2731, NTH2737, NTH2744, NTH2753, NTH2778, NTH2781, NTH2783, NTH2784, NTH2785, NTH2791, NTH2804, NTH2806, NTH2809, NTH2810, and NTH2816.

NTH0861 to NTH0867

Protein NMB0419 from Neisseria meningitidis has been found to participate in the meningococcal invasion mechanism [2]. The protein was shown to modulate bacterial interaction with monolayers of human repiratory epithelial cells, promoting invasion. A homologous protein BPF001 is seen in H. influenzae biogroup aegyptius, but study of this protein was not possible.

The NTHi genome includes a region (SEQ ID NO: 5081) encoding a string of four polypeptides (NTH0861, NTH0863, NTH0865 and NTH0867) with strong similarity to NMB0419. This region and the four polypeptides are shown below:

GCCAGCTTGCTGCCTGCGGTCGACTCTANGAGACCCCTACAACAAAACATAATGCTAAAC AAAAAATGTTTGGTTGTTTCAATTGTTGATTAATAAATGGACGATTTCTATGCGATTCAC                      (SEQ ID NO: 1578) NTH0867   M  R  F  T AAAAACACTTTTTACCACCGCACTTTTAGGTGCTTCTATCTTTTCTTTTCAATCCACCGC  K  T  L  F  T  T  A  L  L  G  A  S  I  F  S  F  Q  S  T  A TTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTCTGAAGCCACTACGAGAGGCGA  W  A  D  T  L  E  Q  Q  F  Q  Q  G  S  E  A  T  T  R  G  D TTATCAAACCACCTTTAAATTTTTGTTACCTCTGGCGGAGCAGGGAAATGCAGAGGCTCA  Y  Q  T  T  F  K  F  L  L  P  L  A  E  Q  G  N  A  E  A  Q ATTGATGTTGGGCGTGATGTATGCAAGAGGAATAGGCGTCAAACAAGATGATTTTGAAGC  L  M  L  G  V  M  Y  A  R  G  I  G  V  K  Q  D  D  F  E  A GGTGAAGTGGTATCGCCAAGCGGCGGAGCAGGGATATGCAAATGCTCAAGCTATATTGGG  V  K  W  Y  R  Q  A  A  E  Q  G  Y  A  N  A  Q  A  I  L  G ATTCTCATATCTTTTAGGACAAAGCGGTGTTCAAGTAAATAAATCTTTAGCCAAAGAATG  F  S  Y  L  L  G  Q  S  G  V  Q  V  N  K  S  L  A  K  E  W GTTTGGTAAGGCTTGTGATAATGGTGATCAAAATGGTTGCGAATATTATGGCAAGTTAAA  F  G  K  A     D  N  G  D  Q  N  G     E  Y  Y  G  K  L  N TAGAGGGGAGCTCTAATGCCAACTTTACAATGCGAATTTTGGAATGTAGGGCAAGGGTTA  R  G  E  L  * TTTTCAAGTGGGCGTATTCAAATGGGAGACGCCCCAGCCTTTCATTGGGTTTATGGTTTG CAAGTTCCTCATCATGGTTCAAAGCCAATTTTAGTGAATAAAAATAAAAGATTATCCATT CATTCAATTTAATAGGAAAACAAATGAAACTCACAAAAACACTTCTTACCACCGCACTTT (SEQ ID NO: 1574)              NTH0865    M  K  L  T  K  T  L  L  T  T  A  L  F TCGGTGCTTCTATTTTTTCTTTTCAATCCACCGCTTGGGCGGATACGCCGGAACAGCAAT   G  A  S  I  F  S  F  Q  S  T  A  W  A  D  T  P  E  Q  Q  F TCCAACAAGGTTTAACCGCTTATGAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGT   Q  Q  G  L  T  A  Y  E  Q  S  N  Y  Q  T  A  F  K  L  W  L TACCTCTGGCGGAGCAGGGAGATGCACAGGCTCAAGGTGGTTTGGGCATGATGTATGAAA   P  L  A  E  Q  G  D  A  Q  A  Q  G  G  L  G  M  M  Y  E  R GAGGACTTGGCGTAAAACAAGAT

CAAAGCAGTGAACTGGTATCGCAAAGCGGCGG   G  L  G  V  K  Q  D  D  F  K  A  V  N  W  Y  R   K  A  A  R AGCAGGGGGATGCAGATGCTCAATTAAATTTGGGTGCGATGTATGCAATCGGACGTGGCG    Q  G   D  A  D  A  Q  L  N  L  G  A  M  Y  A  I  G  R  G  V TAAAACAAGATGGTGT

GGTGAAGTGGTTTCGCAAAGCGGCAGAGCAGGGAAATG   K  Q  D  G  V  E  A  V  K  W  F  R  K  A  A  E  Q  G  N  A CAAAGGCTCAAAATGGTTTGGGCATGATGTATGACGGAGGACTTGGCATAAAACAAGATT   K  A  Q  N  G  L  G  M  M  Y  D  G  G  L  G  I  K  Q  D  Y ATTTCAAAGCGGTGAAATGGCATCGCAAAGCGGCGGAGCAGGGATATGGAGGTGCTCAAG   F  K  A  V  K  W  H  R  K  A  A  E  Q  G  Y  G  G  A  Q  V TTATGTTGGGATTCTCATATCTTTCGGGAAAAGGTGTTCAAGTAAATAAATCTTTAGCCA   M  L  G  F  S  Y  L  S  G  K  G  V  Q  V  N  K  S  L  A  K AAGAATGGTTTGGTAAGGCTTGTGATAATGGTGAACAAGTGGGTTGTGAATATTATGGCA   E  W  F  G  K  A     D  N  G  E  Q  V  G     E  Y  Y  G  K AGCTAAATAGAGGGGAACGCTAATGCCAACTTTACAATGCGAATTTTGGAATGTAGGGCA   L  N  R  G  E  R  * AGGGTTATTTTCAAGTGGGCGTATTCAAATGGGAGACGCCCAAGCCTTTCATTGGGTTTA TGGTTTGCAAGTTCCTCATCATGGTTCAAAGCCAATTTTAGTGAATAAAAATAAAAGATT ATCCATTCATTCAATTTAATAGGAAAACAAA

AAACTCACAAAAACACTTCTTACCAC   (SEQ ID NO: 1570) NTH0863    M  K  L  T  K  T  L  L  T  T CGCACTTTTCGGTGCTTCTGTATTTTCTTTTCAATCCACCGCTTGGGCGGATACGCTGGA  A  L  F  G  A  S  V  F  S  F  Q  S  T  A  W  A  D  T  L  E ACAGCAATTCCAACAAGGTTTAACCGCTTATGAGCAAAGCAACTATCAAACCGCCTTTAA  Q  Q  F  Q  Q  G  L  T  A  Y  E  Q  S  N  Y  Q  T  A  F  K ACTTTGGTTACCTATGGCAGAGCAGGGATATGCAAAGGCTCAATTTAATTTGGGCGTGAT  L  W  L  P  M  A  E  Q  G  Y  A  K  A  Q  F  N  L  G  V  M GTATGCTAAGGGGCAAGGCGTCAAACAAGATG

TGAAGCGGTGAAGTGGTTTCGCAA  Y  A  K  G  Q  G  V  K  Q  D  D  F  E  A  V  K  W  F  R  K AGCGGCGGAGCAGGGATATGCAGAGGCTAAATTTAATTTGGGCCATATGTATTCTAAGGG  A  A  E  Q  G  Y  A  E  A  K  F  N  L  G  H  M  Y  S  K  G ACGAGGCGTCAAACAAGATGATTTTGAAGCAGTGAACTGGTATCGCAAAGCGGCGGAGCA  R  G  V  K  Q  D  D  F  E  A  V  N  W  Y  R  K  A  A  E  Q GGGAGATGCAGATGCTCAAGCTATATTGGGATTCTTATATCTTTTAGGAGAAAGAGGTGT  G  D  A  D  A  Q  A  I  L  G  F  L  Y  L  L  G  E  R  G  V CAAGTAAATAATTCTTTAGCCAAGNAATGGTNTGGTAAGGCTTGTGATAATGGTAATCAA  K  * AATGGCTGCGAATATTATGGCAAGCTAAATAGAGGGGAGCTCTAATGCCCACTTTTACAA TGCGAATTNTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGGCGTATTCAAGTGGAGACG CNNCCAAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCATCATGGTTCANAGCCCAA TTTAGTGNAATAAAAATAAAAGATTATCCATTCATTCAATTTAATAGGAAAACAAAATGA                               (SEQ ID NO: 1566) NTH0861 M  K AACTCACAAAAACACTTCTTACCACCGCACTTTTAGGTGCTTCTGTATTATCTTTTCAAT   L  T  K  T  L  L  T  T  A  L  L  G  A  S  V  L  S  F  Q  S CCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTTAACCGCTTATGAGC   T  A  W  A  D  T  L  E  Q  Q  F  Q  Q  G  L  T  A  Y  E  Q AAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTCTGGCGGAGCAGGGAGATGCAA   S  N  Y  Q  T  A  F  K  L  W  L  P  L  A  E  Q  G  D  A  N ATGTTCAATTTAATTTGGGCGTGATGTATGCTGAGGGGCAAGGCGTCAAACAAGATGATT   V  Q  F  N  L  G  V  M  Y  A  E  G  Q  G  V  K  Q  D  D  F TTGAAGCGGTGAAATGGTATCGCAAAGCGGCGGAGCAGGGAGATGCAAATGCTCAGGCTT   E  A  V  K  W  Y  R  K  A  A  E  Q  G  D  A  N  A  Q  A  Y ATTTAGGTTTGGCTTATACTGAAGGGCGTGGTGTAAGACAAGATTATACCGAAGCGGTGA   L  G  L  A  Y  T  E  G  R  G  V  R  Q  D  Y  T  E  A  V  K AGTGGTTTCGCAAAGCGGCGGAGCAGGGACATGCAAATGCTCAAGCTATATGGGATCTCT   W  F  R  K  A  A  E  Q  G  H  A  N  A  Q  A  I  W  D  L  F TTCTTTAGGGTACCGAGCCGAATCGATCCA   L  *

The four coding sequences are aligned (ClustalW) below:

NTH0863 ATGAAACTCACAAAAACACTTCTTACCACCGCACTTTTCGGTGCTTCTGTATTTTCTTTT NTH0867 ATGCGATTCACAAAAACACTTTTTACCACCGCACTTTTAGGTGCTTCTATCTTTTCTTTT NTH0865 ATGAAACTCACAAAAACACTTCTTACCACCGCACTTTTCGGTGCTTCTATTTTTTCTTTT NTH0861 ATGAAACTCACAAAAACACTTCTTACCACCGCACTTTTAGGTGCTTCTGTATTATCTTTT ***  * ************** **************** ********* * ** ****** NTH0863 CAATCCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTTAACCGCTTAT NTH0867 CAATCCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTCTGAAGCCACT NTH0865 CAATCCACCGCTTGGGCGGATACGCCGGAACAGCAATTCCAACAAGGTTTAACCGCTTAT NTH0861 CAATCCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTTAACCGCTTAT ************************* ***********************     **   * NTH0863 GAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTATGGCAGAGCAGGGATAT NTH0867 ACGAGAGGCGATTATCAAACCACCTTTAAATTTTTGTTACCTCTGGCGGAGCAGGGAAAT NTH0865 GAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTCTGGCGGAGCAGGGAGAT NTH0861 GAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTCTGGCGGAGCAGGGAGAT   *  * ** * ********* ******** *** ******* **** ********* ** NTH0863 GCAAAGGCTCAATTTAATTTGGGCGTGATGTATGCTAAGGGGCAAGGCGTCAAACAAGAT NTH0867 GCAGAGGCTCAATTGATGTTGGGCGTGATGTATGCAAGAGGAATAGGCGTCAAACAAGAT NTH0865 GCACAGGCTCAAGGTGGTTTGGGCATGATGTATGAAAGAGGACTTGGCGTAAAACAAGAT NTH0861 GCAAATGTTCAATTTAATTTGGGCGTGATGTATGCTGAGGGGCAAGGCGTCAAACAAGAT *** * * ****      ****** *********     **    ***** ********* NTH0863 GATTT------------------------------------------------------- NTH0867 GATTT------------------------------------------------------- NTH0865 GATTTCAAAGCAGTGAACTGGTATCGCAAAGCGGCGGAGCAGGGGGATGCAGATGCTCAA NTH0861 GATTT------------------------------------------------------- ***** NTH0863 -----------------------------------------------------TGAAGCG NTH0867 -----------------------------------------------------TGAAGCG NTH0865 TTAAATTTGGGTGCGATGTATGCAATCGGACGTGGCGTAAAACAAGATGGTGTTGAAGCG NTH0861 -----------------------------------------------------TGAAGCG                                                      ******* NTH0863 GTGAAGTGGTTTCGCAAAGCGGCGGAGCAGGGATATGCAGAGGCTAAATTTAATTTGGGC NTH0867 GTGAAGTGGTATCGCCAAGCGGCGGAGCAGGGATATGCAAA------------------- NTH0865 GTGAAGTGGTTTCGCAAAGCGGCAGAGCAGGGAAATGCAAAGGCTCAAAATGGTTTGGGC NTH0861 GTGAAATGGTATCGCAAAGCGGCGGAGCAGGGAGATGCAAA------------------- ***** **** **** ******* ********* ***** * NTH0863 CATATGTATTCTAAGGGACGAGGCGTCAAACAAGATGATTTTGAAGCAGTGAACTGGTAT NTH0867 ------------------------------------------------------------ NTH0865 ATGATGTATGACGGAGGACTTGGCATAAAACAAGATTATTTCAAAGCGGTGAAATGGCAT NTH0861 ------------------------------------------------------------ NTH0863 CGCAAAGCGGCGGAGCAGGGAGATGCAGATGCTCAAGCTATATTGGGATTCTTATATCTT NTH0867 -----------------------------TGCTCAAGCTATATTGGGATTCTCATATCTT NTH0865 CGCAAAGCGGCGGAGCAGGGATATGGAGGTGCTCAAGTTATGTTGGGATTCTCATATCTT NTH0861 -----------------------------TGCTCAGGCTTATTTAGGTTTGGCTTATACT                              ****** * *   ** ** **    ***  * NTH0863 TTAGGAGAAAGAGGTGT-CAAGTAAATAATTCTTTAGCCAAGNAATGGTNTGGTAAGGCT NTH0867 TTAGGACAAAGCGGTGTTCAAGTAAATAAATCTTTAGCCAAAGAATGGTTTGGTAAGGCT NTH0865 TCGGGAAAA---GGTGTTCAAGTAAATAAATCTTTAGCCAAAGAATGGTTTGGTAAGGCT NTH0861 GAAGGGCGT---GGTGTAAGACAAGATTATACCGAAGCGGTGAAGTGGTTTCGCAAAGC-    **       *****   *  * ** *  *   ***     * **** * * ** ** NTH0863 TGTGATAATGGTAATCAAAATGGCTGCGAATATTATGGCAAGCTAAATAGAGGGGAGCTC NTH0867 TGTGATAATGGTGATCAAAATGGTTGCGAATATTATGGCAAGTTAAATAGAGGGGAGCTC NTH0865 TGTGATAATGGTGAACAAGTGGGTTGTGAATATTATGGCAAGCTAAATAGAGGGGAACGC NTH0861 ---------GGCGGAGCAGGGACATGCAAATGCT----CAAGCTATAT----GGGATCTC          **      *      **  ***  *    **** ** **    **** * * NTH0863 TAATGCCCACTTTTACAATGCGAATTNTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGG NTH0867 TAATGCCAACTTT-ACAATGCGAATTTTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGG NTH0865 TAATGCCAACTTT-ACAATGCGAATTTTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGG NTH0861 TTTCTTTAGGGTA-CCGAGCCGAATC----GATCCA------------------------ *          *   * *  *****      **  * NTH0863 CGTATTCAAGTGGAGACGCNNCCAAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCA NTH0867 CGTATTCAAATGG-GAGACGCCCCAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCA NTH0865 CGTATTCAAATGG-GAGACGCCCAAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCA NTH0861 ------------------------------------------------------------ NTH0863 TCATGGTTCANAGCCCAATTTAGTGNAATAAAAATAAAAGATTATCCATTCATTCAATTT NTH0867 TCATGGTTCAAAGCCAATTTTAGTGAA-TAAAAATAAAAGATTATCCATTCATTCAATTT NTH0865 TCATGGTTCAAAGCCAATTTTAGTGAA-TAAAAATAAAAGATTATCCATTCATTCAATTT NTH0861 ------------------------------------------------------------ SEQ ID NO: 5083 NTH0863 AATAGGAAAACAAA SEQ ID NO: 5085 NTH0867 AATAGGAAAACAA- SEQ ID NO: 5084 NTH0865 AATAGGAAAACAAA SEQ ID NO: 5082 NTH0861 --------------

The encoded polypeptides are aligned below, together with the bpf001 and NMB0419 sequences:

NTH0861 ------------MKLTKTLLTTALLG---------ASVLSFQS---TAWADTLEQQFQQG NTH0863 ------------MKLTKTLLTTALFG---------ASVFSFQS---TAWADTLEQQFQQG NTH0865 ------------MKLTKTLLTTALFG---------ASIFSFQS---TAWADTPEQQFQQG NTH0867 ------------MRFTKTLFTTALLG---------ASIFSFQS---TAWADTLEQQFQQG BPF001 ------------MKLTKTLFTSALLG---------ASILSFHP---TVAAMDFGT--QVG NMB0419 ------------MKQTVKWLAAALIALGLNRAVWADDVSDFRENLQAAAQGNAAAQYNLG             *: * . :::**:.          .: .*:    :.         : * NTH0861 LTAYE----QSNYQTAFKLWLPLAEQ-GDANVQFNLGVMYAEGQGVKQDDFEAVKWYRKA NTH0863 LTAYE----QSNYQTAFKLWLPMAEQ-GYAKAQFNLGVMYAKGQGVKQDDFEAVKWFRKA NTH0865 LTAYE----QSNYQTAFKLWLPLAEQ-GDAQAQGGLGMMYERGLGVKQDDFKAVNWYRKA NTH0867 SEATT----RGDYQTTFKFLLPLAEQ-GNAEAQLMLGVMYARGIGVKQDDFEAVKWYRQA BPF001 IDAYR----KNDFAQAAEQFKDAGIVRGDPTAQLFLGRMYYNGEFFKQDYVEAAKWYRKA NMB0419 AMYYKGRGVRRDDAEAVRWYRQAAEQ-GLAQAQYNLGWMYANGRGVRQDDTEAVRWYRQA          : :   : .     .   * . .*  ** ** .*  .:**  :*..*:*:* NTH0861 AEQG-------------------------------------------------------- NTH0863 AEQG-------------------------------------------------------- NTH0865 AEQGDADAQLNLGAMYAIGRGVKQDGVEAVKWFRKAAEQGNAKAQNGLGMMYDGGLGIKQ NTH0867 AEQG-------------------------------------------------------- BPF001 AEQGEEFGLLFLG------------------------------------ETYEDGEGVEK NMB0419 AAQGVVQAQYNLG------------------------------------VIYAEGRGVRQ * ** NTH0861 ----------------DANAQAYLGLAYTEGR-GVRQDYTEAVKWFRKAAEQGHANAQAI NTH0863 ----------------YAEAKFNLGHMYSKGR-GVKQDDFEAVNWYRKAAEQGDADAQAI NTH0865 DYFKAVKWHRKAAEQGYGGAQVMLGFSYLSGK-GVQVNKSLAKEWFGKACDNGEQVGCEY NTH0867 ----------------YANAQAILGFSYLLGQSGVQVNKSLAKEWFGKACDNGDQNGCEY BPF001 DYAEAAKLYRKAAEQGSAEGQMALGKMYRFGN-GVEKDYAEAIKLYRKSAEQGNFTALFF NMB0419 DDVEAVRWFRQAAAQGVAQAQNNLGVMYAERR-GVRQDRALAQEWFGKACQNGDQDGCDN                  . .:  **  *   . **. :   * : : *:.::*.  . SEQ ID NO: 1566 NTH0861 WDLFL----------------- SEQ ID NO: 1570 NTH0863 LGFLYLLGERGVK--------- SEQ ID NO: 1574 NTH0865 YGKLNR-GER------------ SEQ ID NO: 1578 NTH0867 YGKLNR-GEL------------ SEQ ID NO: 5086 BPF001 LGEMYDNGVGVKQNKAESQRII SEQ ID NO: 5087 NMB0419 DQRLKAGY--------------    :

The serial repeats of four closely-related genes that are also related to genes involved in bacterial invasion is noteworthy, and NTH0861, NTH0863, NTH0865 and NTH0867 are of particular interest for immunisation purposes. NTH0867 in particular is an outer-membrane protein that is not seen in the Rd genome, and is of special interest.

Moreover, as well as being caused by NTHi, acute otitis media is often caused by Moraxella catarrhalis and Streptococcus pneumoniae. Four proteins have been identified that in the NTHi genome that have homologs in the M. catarrhalis genome, namely NTH0861 (SEQ ID NO: 1566), NTH0863 (SEQ ID NO: 1570), NTH0865 (SEQ ID NO: 1574) and NTH0867 (SEQ ID NO: 1578). These proteins can thus be used as antigens for a general AOM vaccine. The corresponding M. catarrhalis antigens can also be used, either on their own or in combination with the NTHi antigens.

A variant of SEQ ID NO: 1566 is given as SEQ ID NO: 5095:

A variant of SEQ ID NO: 1570 is given as SEQ ID NO: 5094:

A variant of SEQ ID NO: 1574 is given as SEQ ID NO: 5093:

A variant of SEQ ID NO: 1578 is given as SEQ ID NO: 5092:

Preferred NTH0861 proteins have identity to both of SEQ ID NOS: 1566 and 5095. Preferred NTH0863 proteins have identity to both of SEQ ID NOS: 1570 and 5094. Preferred NTH0865 proteins have identity to both of SEQ ID NOS: 1574 and 5093. Preferred NTH0867 proteins have identity to both of SEQ ID NOS: 1578 and 5092.

It will be understood that the invention has been described by way of example only and modifications may be made whilst remaining within the scope and spirit of the invention.

TABLE I MISSING NTHnnnn VALUES between NTH0001 and NTH2832 0008 0031 0042 0054 0056 0066 0074 0077 0093 0111 0160 0162 0166 0171 0179 0210 0213 0214 0219 0229 0231 0276 0281 0288 0293 0322 0332 0357 0362 0381 0395 0398 0404 0406 0409 0410 0415 0439 0445 0446 0452 0466 0471 0491 0497 0516 0533 0538 0541 0546 0551 0553 0556 0569 0578 0598 0600 0610 0623 0639 0649 0666 0693 0713 0722 0727 0742 0746 0757 0763 0780 0789 0791 0793 0800 0809 0816 0855 0883 0891 0902 0911 0915 0916 0922 0943 0944 0957 0975 0978 0980 0998 0999 1013 1034 1044 1047 1055 1056 1065 1072 1076 1079 1099 1113 1118 1119 1128 1133 1134 1136 1146 1147 1158 1160 1170 1194 1199 1213 1219 1223 1232 1243 1257 1260 1288 1289 1296 1312 1317 1329 1335 1347 1350 1356 1358 1362 1364 1372 1377 1385 1452 1458 1469 1478 1481 1486 1488 1502 1517 1518 1529 1536 1547 1553 1557 1560 1566 1592 1595 1596 1604 1642 1649 1667 1669 1674 1691 1699 1711 1715 1721 1723 1727 1728 1731 1737 1741 1743 1746 1750 1761 1772 1784 1797 1810 1814 1823 1843 1844 1856 1864 1866 1878 1902 1909 1918 1957 1961 1979 1985 1987 1990 2004 2006 2015 2017 2023 2033 2037 2042 2054 2077 2080 2098 2104 2107 2125 2154 2167 2171 2174 2179 2194 2203 2210 2218 2237 2239 2240 2244 2254 2255 2267 2268 2270 2275 2278 2286 2290 2295 2300 2302 2312 2320 2334 2340 2355 2357 2366 2367 2374 2380 2400 2409 2431 2444 2459 2523 2540 2547 2551 2574 2580 2589 2601 2611 2614 2624 2628 2637 2639 2645 2652 2658 2662 2677 2692 2699 2700 2728 2734 2746 2760 2767 2773 2787 2799 2805 2808 2819 2822

TABLE II Preferred polypeptides NTH0001 NTH0002 NTH0004 NTH0005 NTH0012 NTH0014 NTH0015 NTH0016 NTH0017 NTH0019 NTH0020 NTH0021 NTH0022 NTH0024 NTH0025 NTH0032 NTH0033 NTH0034 NTH0035 NTH0036 NTH0037 NTH0038 NTH0040 NTH0041 NTH0043 NTH0045 NTH0048 NTH0049 NTH0050 NTH0051 NTH0052 NTH0053 NTH0057 NTH0059 NTH0060 NTH0061 NTH0064 NTH0067 NTH0073 NTH0076 NTH0085 NTH0089 NTH0091 NTH0092 NTH0094 NTH0097 NTH0101 NTH0104 NTH0106 NTH0107 NTH0110 NTH0114 NTH0116 NTH0118 NTH0119 NTH0120 NTH0121 NTH0122 NTH0123 NTH0124 NTH0125 NTH0128 NTH0129 NTH0132 NTH0134 NTH0135 NTH0136 NTH0138 NTH0140 NTH0146 NTH0148 NTH0151 NTH0153 NTH0154 NTH0155 NTH0157 NTH0158 NTH0159 NTH0161 NTH0163 NTH0164 NTH0167 NTH0169 NTH0173 NTH0174 NTH0176 NTH0177 NTH0180 NTH0184 NTH0185 NTH0186 NTH0187 NTH0189 NTH0190 NTH0191 NTH0192 NTH0193 NTH0194 NTH0195 NTH0197 NTH0198 NTH0199 NTH0203 NTH0206 NTH0208 NTH0209 NTH0223 NTH0224 NTH0226 NTH0227 NTH0228 NTH0232 NTH0235 NTH0236 NTH0237 NTH0238 NTH0241 NTH0242 NTH0244 NTH0247 NTH0248 NTH0250 NTH0251 NTH0252 NTH0253 NTH0254 NTH0255 NTH0256 NTH0263 NTH0264 NTH0265 NTH0269 NTH0270 NTH0278 NTH0279 NTH0280 NTH0282 NTH0283 NTH0284 NTH0285 NTH0289 NTH0290 NTH0295 NTH0297 NTH0298 NTH0299 NTH0300 NTH0302 NTH0307 NTH0308 NTH0310 NTH0311 NTH0312 NTH0313 NTH0317 NTH0319 NTH0320 NTH0321 NTH0325 NTH0326 NTH0327 NTH0328 NTH0331 NTH0333 NTH0334 NTH0335 NTH0339 NTH0341 NTH0346 NTH0347 NTH0348 NTH0351 NTH0352 NTH0353 NTH0356 NTH0358 NTH0363 NTH0366 NTH0371 NTH0372 NTH0375 NTH0378 NTH0379 NTH0384 NTH0385 NTH0388 NTH0396 NTH0397 NTH0400 NTH0401 NTH0402 NTH0405 NTH0407 NTH0408 NTH0411 NTH0412 NTH0417 NTH0418 NTH0419 NTH0420 NTH0421 NTH0424 NTH0426 NTH0427 NTH0429 NTH0430 NTH0431 NTH0432 NTH0433 NTH0434 NTH0435 NTH0437 NTH0438 NTH0444 NTH0453 NTH0455 NTH0457 NTH0459 NTH0460 NTH0461 NTH0462 NTH0463 NTH0465 NTH0468 NTH0469 NTH0473 NTH0475 NTH0478 NTH0484 NTH0485 NTH0486 NTH0487 NTH0488 NTH0489 NTH0490 NTH0493 NTH0496 NTH0498 NTH0500 NTH0501 NTH0502 NTH0504 NTH0506 NTH0507 NTH0509 NTH0510 NTH0511 NTH0512 NTH0513 NTH0518 NTH0520 NTH0523 NTH0524 NTH0526 NTH0527 NTH0528 NTH0529 NTH0531 NTH0534 NTH0536 NTH0539 NTH0544 NTH0545 NTH0547 NTH0549 NTH0559 NTH0561 NTH0565 NTH0566 NTH0573 NTH0574 NTH0577 NTH0579 NTH0580 NTH0581 NTH0582 NTH0583 NTH0584 NTH0585 NTH0586 NTH0587 NTH0588 NTH0590 NTH0599 NTH0603 NTH0604 NTH0606 NTH0615 NTH0617 NTH0618 NTH0619 NTH0622 NTH0624 NTH0626 NTH0630 NTH0631 NTH0636 NTH0637 NTH0638 NTH0642 NTH0643 NTH0644 NTH0645 NTH0646 NTH0647 NTH0648 NTH0653 NTH0654 NTH0656 NTH0658 NTH0661 NTH0662 NTH0663 NTH0664 NTH0667 NTH0668 NTH0673 NTH0675 NTH0676 NTH0677 NTH0678 NTH0680 NTH0681 NTH0683 NTH0687 NTH0690 NTH0691 NTH0692 NTH0694 NTH0695 NTH0696 NTH0702 NTH0703 NTH0706 NTH0707 NTH0709 NTH0710 NTH0711 NTH0712 NTH0715 NTH0716 NTH0717 NTH0718 NTH0721 NTH0724 NTH0725 NTH0726 NTH0728 NTH0729 NTH0730 NTH0738 NTH0740 NTH0744 NTH0745 NTH0749 NTH0750 NTH0752 NTH0755 NTH0756 NTH0762 NTH0764 NTH0765 NTH0768 NTH0771 NTH0774 NTH0776 NTH0788 NTH0792 NTH0794 NTH0795 NTH0796 NTH0797 NTH0798 NTH0802 NTH0803 NTH0804 NTH0813 NTH0814 NTH0815 NTH0818 NTH0820 NTH0821 NTH0822 NTH0827 NTH0829 NTH0832 NTH0834 NTH0835 NTH0836 NTH0838 NTH0839 NTH0841 NTH0843 NTH0844 NTH0848 NTH0849 NTH0850 NTH0851 NTH0852 NTH0856 NTH0858 NTH0861 NTH0862 NTH0863 NTH0864 NTH0865 NTH0866 NTH0867 NTH0872 NTH0874 NTH0875 NTH0877 NTH0879 NTH0880 NTH0885 NTH0886 NTH0887 NTH0888 NTH0892 NTH0894 NTH0895 NTH0896 NTH0900 NTH0901 NTH0904 NTH0906 NTH0909 NTH0910 NTH0913 NTH0914 NTH0921 NTH0924 NTH0926 NTH0927 NTH0928 NTH0929 NTH0930 NTH0931 NTH0932 NTH0933 NTH0937 NTH0938 NTH0941 NTH0942 NTH0948 NTH0949 NTH0950 NTH0952 NTH0953 NTH0955 NTH0961 NTH0964 NTH0968 NTH0970 NTH0971 NTH0972 NTH0973 NTH0985 NTH0986 NTH0987 NTH0989 NTH0991 NTH0992 NTH0993 NTH0994 NTH0995 NTH0996 NTH0997 NTH1000 NTH1002 NTH1003 NTH1004 NTH1005 NTH1007 NTH1009 NTH1010 NTH1012 NTH1015 NTH1016 NTH1017 NTH1018 NTH1020 NTH1021 NTH1025 NTH1026 NTH1027 NTH1028 NTH1029 NTH1031 NTH1032 NTH1037 NTH1039 NTH1040 NTH1042 NTH1043 NTH1048 NTH1049 NTH1052 NTH1054 NTH1058 NTH1063 NTH1064 NTH1067 NTH1069 NTH1070 NTH1073 NTH1075 NTH1080 NTH1082 NTH1083 NTH1084 NTH1085 NTH1086 NTH1087 NTH1089 NTH1090 NTH1091 NTH1092 NTH1098 NTH1102 NTH1103 NTH1104 NTH1106 NTH1108 NTH1111 NTH1112 NTH1114 NTH1115 NTH1116 NTH1121 NTH1122 NTH1123 NTH1124 NTH1125 NTH1129 NTH1130 NTH1131 NTH1138 NTH1141 NTH1142 NTH1149 NTH1150 NTH1151 NTH1153 NTH1157 NTH1159 NTH1161 NTH1162 NTH1164 NTH1174 NTH1176 NTH1178 NTH1179 NTH1181 NTH1184 NTH1185 NTH1188 NTH1189 NTH1190 NTH1191 NTH1192 NTH1193 NTH1195 NTH1196 NTH1200 NTH1201 NTH1203 NTH1204 NTH1205 NTH1207 NTH1208 NTH1209 NTH1210 NTH1211 NTH1214 NTH1216 NTH1220 NTH1221 NTH1224 NTH1225 NTH1226 NTH1229 NTH1230 NTH1231 NTH1233 NTH1234 NTH1235 NTH1236 NTH1237 NTH1238 NTH1240 NTH1241 NTH1244 NTH1245 NTH1246 NTH1247 NTH1248 NTH1249 NTH1250 NTH1251 NTH1252 NTH1253 NTH1254 NTH1255 NTH1256 NTH1261 NTH1262 NTH1268 NTH1270 NTH1271 NTH1273 NTH1275 NTH1279 NTH1280 NTH1281 NTH1282 NTH1283 NTH1286 NTH1287 NTH1290 NTH1293 NTH1294 NTH1295 NTH1297 NTH1298 NTH1299 NTH1300 NTH1301 NTH1302 NTH1305 NTH1306 NTH1307 NTH1308 NTH1309 NTH1311 NTH1313 NTH1315 NTH1316 NTH1319 NTH1321 NTH1325 NTH1327 NTH1330 NTH1332 NTH1333 NTH1334 NTH1336 NTH1337 NTH1339 NTH1341 NTH1342 NTH1346 NTH1348 NTH1353 NTH1354 NTH1357 NTH1359 NTH1361 NTH1363 NTH1365 NTH1367 NTH1368 NTH1374 NTH1375 NTH1376 NTH1379 NTH1380 NTH1381 NTH1382 NTH1383 NTH1388 NTH1390 NTH1391 NTH1393 NTH1394 NTH1395 NTH1396 NTH1398 NTH1399 NTH1400 NTH1406 NTH1407 NTH1411 NTH1412 NTH1413 NTH1414 NTH1415 NTH1416 NTH1418 NTH1419 NTH1420 NTH1421 NTH1425 NTH1427 NTH1428 NTH1429 NTH1430 NTH1431 NTH1434 NTH1435 NTH1437 NTH1438 NTH1439 NTH1441 NTH1447 NTH1448 NTH1450 NTH1454 NTH1455 NTH1456 NTH1464 NTH1467 NTH1468 NTH1470 NTH1471 NTH1472 NTH1473 NTH1474 NTH1479 NTH1487 NTH1489 NTH1490 NTH1491 NTH1492 NTH1493 NTH1494 NTH1495 NTH1496 NTH1497 NTH1500 NTH1503 NTH1504 NTH1506 NTH1510 NTH1515 NTH1516 NTH1525 NTH1526 NTH1527 NTH1528 NTH1531 NTH1532 NTH1537 NTH1538 NTH1540 NTH1541 NTH1543 NTH1548 NTH1552 NTH1555 NTH1559 NTH1562 NTH1563 NTH1564 NTH1567 NTH1569 NTH1570 NTH1571 NTH1573 NTH1574 NTH1575 NTH1580 NTH1581 NTH1582 NTH1584 NTH1586 NTH1587 NTH1588 NTH1590 NTH1594 NTH1597 NTH1598 NTH1599 NTH1600 NTH1601 NTH1602 NTH1603 NTH1605 NTH1606 NTH1607 NTH1608 NTH1609 NTH1611 NTH1612 NTH1615 NTH1616 NTH1617 NTH1618 NTH1619 NTH1620 NTH1621 NTH1622 NTH1623 NTH1625 NTH1626 NTH1627 NTH1628 NTH1629 NTH1631 NTH1634 NTH1637 NTH1638 NTH1647 NTH1652 NTH1653 NTH1654 NTH1656 NTH1657 NTH1658 NTH1662 NTH1664 NTH1666 NTH1668 NTH1671 NTH1675 NTH1676 NTH1677 NTH1680 NTH1686 NTH1687 NTH1688 NTH1689 NTH1690 NTH1692 NTH1693 NTH1697 NTH1698 NTH1701 NTH1702 NTH1703 NTH1707 NTH1712 NTH1713 NTH1718 NTH1719 NTH1722 NTH1724 NTH1725 NTH1729 NTH1732 NTH1734 NTH1735 NTH1739 NTH1740 NTH1742 NTH1744 NTH1745 NTH1748 NTH1749 NTH1751 NTH1752 NTH1753 NTH1754 NTH1755 NTH1756 NTH1757 NTH1758 NTH1759 NTH1760 NTH1765 NTH1767 NTH1769 NTH1770 NTH1773 NTH1778 NTH1779 NTH1781 NTH1782 NTH1783 NTH1788 NTH1793 NTH1795 NTH1796 NTH1798 NTH1799 NTH1803 NTH1804 NTH1805 NTH1806 NTH1807 NTH1811 NTH1812 NTH1813 NTH1815 NTH1816 NTH1817 NTH1818 NTH1819 NTH1820 NTH1821 NTH1822 NTH1824 NTH1828 NTH1829 NTH1832 NTH1833 NTH1835 NTH1836 NTH1837 NTH1842 NTH1845 NTH1849 NTH1850 NTH1854 NTH1857 NTH1859 NTH1861 NTH1865 NTH1870 NTH1871 NTH1872 NTH1873 NTH1881 NTH1882 NTH1885 NTH1888 NTH1889 NTH1891 NTH1892 NTH1896 NTH1897 NTH1898 NTH1899 NTH1900 NTH1904 NTH1906 NTH1908 NTH1910 NTH1914 NTH1916 NTH1917 NTH1919 NTH1920 NTH1921 NTH1922 NTH1923 NTH1925 NTH1927 NTH1935 NTH1939 NTH1941 NTH1942 NTH1945 NTH1946 NTH1947 NTH1948 NTH1951 NTH1953 NTH1956 NTH1958 NTH1960 NTH1962 NTH1963 NTH1964 NTH1965 NTH1966 NTH1967 NTH1968 NTH1974 NTH1978 NTH1981 NTH1986 NTH1989 NTH1992 NTH1993 NTH1994 NTH1995 NTH1996 NTH1997 NTH1998 NTH1999 NTH2001 NTH2005 NTH2008 NTH2009 NTH2010 NTH2019 NTH2024 NTH2025 NTH2031 NTH2035 NTH2038 NTH2039 NTH2040 NTH2041 NTH2043 NTH2050 NTH2052 NTH2055 NTH2056 NTH2060 NTH2062 NTH2064 NTH2065 NTH2069 NTH2070 NTH2071 NTH2073 NTH2075 NTH2078 NTH2079 NTH2081 NTH2083 NTH2089 NTH2091 NTH2092 NTH2093 NTH2094 NTH2095 NTH2096 NTH2097 NTH2099 NTH2101 NTH2109 NTH2110 NTH2112 NTH2113 NTH2114 NTH2115 NTH2116 NTH2117 NTH2118 NTH2119 NTH2120 NTH2122 NTH2126 NTH2128 NTH2129 NTH2130 NTH2131 NTH2133 NTH2135 NTH2136 NTH2138 NTH2142 NTH2145 NTH2146 NTH2149 NTH2150 NTH2156 NTH2159 NTH2162 NTH2163 NTH2166 NTH2169 NTH2170 NTH2173 NTH2181 NTH2183 NTH2187 NTH2191 NTH2193 NTH2195 NTH2196 NTH2197 NTH2198 NTH2199 NTH2200 NTH2204 NTH2205 NTH2206 NTH2207 NTH2209 NTH2213 NTH2216 NTH2217 NTH2219 NTH2220 NTH2221 NTH2222 NTH2223 NTH2226 NTH2227 NTH2228 NTH2229 NTH2231 NTH2232 NTH2234 NTH2235 NTH2242 NTH2243 NTH2245 NTH2247 NTH2250 NTH2251 NTH2253 NTH2256 NTH2257 NTH2258 NTH2259 NTH2262 NTH2263 NTH2266 NTH2269 NTH2273 NTH2274 NTH2277 NTH2282 NTH2284 NTH2285 NTH2287 NTH2288 NTH2291 NTH2292 NTH2296 NTH2299 NTH2305 NTH2309 NTH2315 NTH2316 NTH2318 NTH2323 NTH2324 NTH2326 NTH2327 NTH2330 NTH2332 NTH2333 NTH2342 NTH2343 NTH2344 NTH2346 NTH2347 NTH2349 NTH2352 NTH2353 NTH2356 NTH2358 NTH2361 NTH2362 NTH2363 NTH2364 NTH2365 NTH2368 NTH2369 NTH2370 NTH2371 NTH2376 NTH2377 NTH2381 NTH2382 NTH2386 NTH2388 NTH2394 NTH2398 NTH2402 NTH2405 NTH2406 NTH2407 NTH2408 NTH2414 NTH2414 NTH2422 NTH2430 NTH2432 NTH2433 NTH2434 NTH2438 NTH2442 NTH2447 NTH2448 NTH2451 NTH2455 NTH2456 NTH2457 NTH2458 NTH2460 NTH2461 NTH2463 NTH2464 NTH2466 NTH2467 NTH2468 NTH2471 NTH2472 NTH2478 NTH2480 NTH2481 NTH2482 NTH2483 NTH2484 NTH2485 NTH2486 NTH2487 NTH2488 NTH2493 NTH2495 NTH2496 NTH2497 NTH2498 NTH2499 NTH2500 NTH2501 NTH2505 NTH2508 NTH2510 NTH2524 NTH2525 NTH2527 NTH2528 NTH2531 NTH2532 NTH2533 NTH2534 NTH2536 NTH2537 NTH2541 NTH2542 NTH2543 NTH2545 NTH2546 NTH2548 NTH2549 NTH2550 NTH2552 NTH2554 NTH2556 NTH2557 NTH2558 NTH2562 NTH2563 NTH2566 NTH2567 NTH2568 NTH2569 NTH2570 NTH2572 NTH2573 NTH2575 NTH2577 NTH2578 NTH2584 NTH2585 NTH2587 NTH2588 NTH2590 NTH2591 NTH2593 NTH2595 NTH2597 NTH2600 NTH2602 NTH2603 NTH2604 NTH2605 NTH2607 NTH2608 NTH2609 NTH2610 NTH2612 NTH2613 NTH2615 NTH2616 NTH2618 NTH2626 NTH2633 NTH2635 NTH2640 NTH2641 NTH2647 NTH2648 NTH2649 NTH2650 NTH2655 NTH2661 NTH2663 NTH2664 NTH2667 NTH2668 NTH2673 NTH2674 NTH2675 NTH2679 NTH2680 NTH2684 NTH2690 NTH2693 NTH2694 NTH2696 NTH2697 NTH2701 NTH2702 NTH2703 NTH2704 NTH2705 NTH2706 NTH2707 NTH2708 NTH2709 NTH2710 NTH2711 NTH2712 NTH2713 NTH2715 NTH2716 NTH2718 NTH2719 NTH2720 NTH2721 NTH2723 NTH2724 NTH2725 NTH2726 NTH2727 NTH2729 NTH2730 NTH2731 NTH2732 NTH2735 NTH2737 NTH2738 NTH2740 NTH2743 NTH2744 NTH2749 NTH2750 NTH2753 NTH2754 NTH2755 NTH2756 NTH2757 NTH2758 NTH2764 NTH2765 NTH2769 NTH2774 NTH2777 NTH2778 NTH2779 NTH2781 NTH2783 NTH2784 NTH2785 NTH2791 NTH2793 NTH2794 NTH2796 NTH2797 NTH2798 NTH2804 NTH2806 NTH2807 NTH2809 NTH2810 NTH2813 NTH2814 NTH2816 NTH2823

TABLE III Annotations aa = length of polypeptide PSORT = cellular location of polypeptide, according to PSORT algorithm NTH aa PSORT Annotation 0003 274 cytoplasm Diaminopimelate epimerase (dapF) 0007 61 cytoplasm tldD protein tldD 0010 158 cytoplasm transcriptional regulator 0011 93 cytoplasm usg-1 protein (usg1) 0013 274 cytoplasm excinuclease ABC, subunit C (uvrC) 0014 64 periplasmic excinuclease ABC, subunit C (uvrC) 0017 161 outer 2′,3′-cyclic-nucleotide 2′-phosphodiesterase (cpdB) 0018 130 cytoplasm 16s pseudouridylate 516 synthase (rsuA) 0019 98 inner 1 bicyclomycin resistance protein (bcr) 0020 181 inner 4 Na(+)-translocating NADH-quinone reductase, subunit 0023 110 cytoplasm sigma-E factor regulatory protein (rseB) 0025 195 inner 1 sigma-E factor negative regulatory protein (mclA) 0026 157 cytoplasm RNA polymerase sigma-E factor (rpoE) 0027 100 cytoplasm cell division protein (ftsQ) 0028 37 cytoplasm cell division protein (ftsA) 0029 34 cytoplasm cell division protein (ftsA) 0030 268 cytoplasm aspartate--ammonia ligase (asnA) 0039 311 cytoplasm ADP-heptose--LPS heptosyltransferase II (rfaF) 0043 194 inner 3 sodium:dicarboxylate symporter protein 0044 79 cytoplasm ferritin (rsgA) 0047 219 cytoplasm heat shock protein (hslU)/ATP-dependent Clp protease, ATP-binding subunit 0048 55 inner 2 L-lactate permease (lctP) 0049 90 periplasmic transferrin-binding protein or TonB-dependent receptor 0055 92 cytoplasm heat shock protein (hslV) 0057 235 periplasmic acid phosphatase 0058 206 cytoplasm rod shape-determining protein (mreB) or cell division protein FtsA ftsA 0059 54 periplasmic rod shape-determining protein (mreC) 0060 104 inner 0 ribosomal protein S8 (rpS8) 0061 313 inner 2 ribosomal protein L6 (rpL6) 0063 257 cytoplasm fumarate (and nitrate) reduction regulatory protein (fnr) 0065 266 cytoplasm thiamin ABC transporter, periplasmic-binding protein (tbpA) 0067 86 inner 1 thiamin ABC transporter, permease protein 0068 52 cytoplasm UDP-N-acetylenolpyruvoylglucosamine reductase (murB) 0069 149 cytoplasm RNA polymerase sigma-32 factor (rpoH) 0070 127 cytoplasm RNA polymerase sigma-32 factor (rpoH) 0071 64 cytoplasm NifR3/SMM1 family protein 0072 201 cytoplasm acetolactate synthase III large subunit (ilvI) 0073 142 inner 1 acetolactate synthase III large subunit (ilvI) 0075 166 cytoplasm acetolactate synthase III small subunit (ilvH) 0078 119 cytoplasm orotate phosphoribosyltransferase (pyrE) 0079 36 cytoplasm orotate phosphoribosyltransferase (pyrE) 0082 144 cytoplasm DNA polymerase III, chi subunit (holC) 0083 85 cytoplasm methylglyoxal synthase (mgsA) 0085 340 inner 7 cytochrome C-type biogenesis protein (ccmF) 0086 45 cytoplasm cytochrome C-type biogenesis protein (ccmE) 0087 312 cytoplasm histidyl-tRNA synthetase (hisS) 0088 214 cytoplasm topoisomerase IV, subunit A (parC) 0091 212 inner 1 4-hydroxy-2-oxoglutarate 0094 338 lipo zinc protease 0098 358 cytoplasm homoserine O-acetyltransferase (met2) 0099 60 cytoplasm DNA gyrase, subunit A (gyrA) 0100 56 cytoplasm DNA gyrase, subunit A (gyrA) 0102 102 cytoplasm universal stress protein A (uspA) 0103 290 cytoplasm alanyl-tRNA synthetase (alaS) 0104 81 cytoplasm alanyl-tRNA synthetase (alaS) 0105 557 cytoplasm protective surface antigen D15 (Omp85) 0106 110 periplasmic outer membrane protein 0107 257 inner 1 cell division protein (ftsZ) 0108 352 cytoplasm cell division protein (ftsA) 0109 496 cytoplasm DNA topoisomerase I (topA) 0112 259 cytoplasm penicillin-binding protein 1B (ponB) 0113 35 cytoplasm penicillin-binding protein 1B (ponB) 0115 279 cytoplasm penicillin-binding protein 1A (ponA) 0116 310 inner 1 GTP-binding protein 0117 243 cytoplasm phosphomannomutase (yhxB) 0118 84 inner 0 phosphomannomutase (yhxB) 0119 89 periplasmic tonB protein 0120 147 periplasmic biopolymer transport protein (exbD) 0121 49 inner 1 biopolymer transport protein (exbB) 0126 77 cytoplasm integrase/recombinase 0128 111 inner 1 xanthine-guanine phosphoribosyltransferase (gptB) 0130 184 cytoplasm aminoacyl-histidine dipeptidase (pepD) 0131 35 cytoplasm aminoacyl-histidine dipeptidase (pepD) 0134 182 inner 1 phosphoribosylglycinamide formyltransferase (purN) 0137 58 cytoplasm GTP-binding membrane protein (lepA) 0141 78 cytoplasm uracil DNA glycosylase (ung) 0142 76 cytoplasm aldose 1-epimerase (galM) 0143 129 cytoplasm galactokinase (galK) 0144 197 cytoplasm galactokinase (galK) 0145 346 cytoplasm GTP-binding protein TypA 0147 179 cytoplasm queuine tRNA-ribosyltransferase (tgt) 0150 239 cytoplasm ribosomal large subunit pseudouridine synthase C 0152 463 cytoplasm galactoside ABC transporter, ATP-binding protein (mglA) 0153 247 cytoplasm hemagglutinin/hemolysin-related protein 0154 240 cytoplasm hemagglutinin/hemolysin-related protein 0155 302 inner 7 phosphate permease 0157 124 inner 2 cytochrome D ubiquinol oxidase, subunit I (cydA) or iron(III) ABC transporter, permease protein fbpB 0158 103 inner 2 cytochrome D ubiquinol oxidase, subunit II (cydB) 0163 154 lipo 15 kDa peptidoglycan-associated lipoprotein (lpp) 0165 165 cytoplasm membrane-bound lytic murein transglycosylase C (mltC) 0167 194 lipo membrane-bound lytic murein transglycosylase C (mltC) 0170 51 cytoplasm hflK protein (hflK) 0174 40 periplasmic tail specific protease (prc) 0178 116 cytoplasm recombination protein (rec2) or competence protein ComA comA 0180 147 inner 2 ABC transporter, ATP-binding protein (msbA) 0185 220 inner 0 chorismate synthase (aroC) 0186 156 inner 2 ATP-binding transport protein (cydD) 0189 162 inner 2 rod shape-determining protein (mreD) 0190 188 periplasmic rod shape-determining protein (mreC) 0196 68 cytoplasm sigma factor 0200 68 cytoplasm mercuric ion scavenger protein (merP) 0201 68 cytoplasm mercuric ion scavenger protein (merP) 0202 68 cytoplasm mercuric ion scavenger protein (merP) 0203 63 inner 0 orfJ protein 0204 306 cytoplasm penicillin-binding protein 1A (ponA) 0205 38 cytoplasm penicillin-binding protein 1A (ponA) 0207 175 cytoplasm extragenic suppressor (suhB) 0208 64 inner 1 cytochrome C-type biogenesis 0209 117 inner 2 1,4-dihydroxy-2-naphthoate octaprenyltransferase (menA) 0212 203 cytoplasm lysyl-tRNA synthetase analog (genX) 0215 204 cytoplasm fumarate reductase, flavoprotein subunit (frdA) or succinate dehydrogenase, flavoprotein subunit sdhA 0216 48 cytoplasm fumarate reductase, flavoprotein subunit (frdA) 0217 40 cytoplasm fumarate reductase, flavoprotein subunit (frdA) 0218 310 cytoplasm nitrogen fixation protein (nifR3) 0220 99 cytoplasm Hin recombinational enhancer binding protein (fis) or factor-for-inversion stimulation protein Fis, 0221 48 cytoplasm small protein B (smpB) 0222 222 cytoplasm magnesium and cobalt transport protein (corA) 0223 91 inner 1 magnesium and cobalt transport protein (corA) 0225 426 cytoplasm exoribonuclease II (rnb) or ribonuclease II family protein vacB 0233 114 cytoplasm uridylate kinase (pyrH) 0234 41 cytoplasm uridylate kinase (pyrH) 0236 35 cytoplasm phospho-2-dehydro-3-deoxyheptonate aldolase (phenylalanine 0239 322 cytoplasm heat shock (chaperone) protein (hscA) 0240 44 cytoplasm heat shock (chaperone) protein (hscA) 0241 193 outer usg-1 protein (usg1) 0242 268 inner 2 tryptophan synthase alpha subunit (trpA) 0243 58 cytoplasm tryptophan synthase beta subunit (trpB) 0244 245 periplasmic stationary phase survival protein SurA or peptidyl-prolyl cis-trans isomerase 0245 191 cytoplasm pyrimidine operon regulatory protein (pyrR) or hypoxanthine-guanine phosphoribosyltransferase, 0246 153 cytoplasm mazG protein (mazG) 0247 159 inner 3 ATP synthase F0, subunit a (atpB) 0249 203 cytoplasm glucose-inhibited division protein (gidB) 0257 289 cytoplasm selenocysteine-specific elongation factor (selB) 0258 212 cytoplasm pyruvate dehydrogenase, E1 component (aceE) 0259 61 cytoplasm pyruvate dehydrogenase, E1 component (aceE) 0260 505 cytoplasm ribonuclease E (rne) 0262 303 cytoplasm ATP-dependent helicase (dinG) 0263 276 inner 7 thiamin ABC transporter, permease protein 0266 121 cytoplasm N utilization substance protein B (nusB) 0267 160 cytoplasm thiamin-monophosphate kinase (thiL) 0268 144 cytoplasm thiamin-monophosphate kinase (thiL) 0269 163 inner 3 phosphatidylglycerophosphatase A (pgpA) 0272 44 cytoplasm ribosomal protein L34 (rpL34) 0273 119 cytoplasm ribonuclease P (rnpA) 0275 146 cytoplasm impA protein 0277 218 cytoplasm phospho-2-dehydro-3-deoxyheptonate aldolase (phenylalanine 0286 288 cytoplasm GTP-binding protein 0287 422 cytoplasm formate dehydrogenase, beta subunit (fdxH) or ferredoxin, 4Fe—4S bacterial type 0291 109 cytoplasm mannonate dehydratase (uxuA) 0292 46 cytoplasm mannonate dehydratase (uxuA) 0294 171 cytoplasm dihydroxyacid dehydratase (ilvD) 0295 308 inner 1 threonine deaminase (ilvA) 0296 239 cytoplasm galactose-1-phosphate uridylyltransferase (galT) 0303 283 cytoplasm hemoglobin-binding protein 0304 68 cytoplasm ribosomal protein L24 (rpL24) 0305 123 cytoplasm ribosomal protein L14 (rpL14) 0309 82 cytoplasm inorganic pyrophosphatase (ppa) 0311 185 inner 4 phosphatidylglycerophosphate synthase (pgsA) or CDP-diacylglycerol-- glycerol-3-phosphate 0314 274 cytoplasm dihydrolipoamide dehydrogenase (lpdA) or pyruvate dehydrogenase, E3 component, lipoamide 0315 38 cytoplasm dihydrolipoamide dehydrogenase (lpdA) 0318 358 cytoplasm DNA topoisomerase III (topB) or DNA topoisomerase I topA 0320 411 inner 1 Nqr6 subunit of Na-translocating NADH-quinone reductase 0321 191 inner 1 single-stranded DNA binding protein (ssb) 0323 141 cytoplasm excinuclease ABC, subunit A (uvrA) 0324 319 cytoplasm type IV pilus assembly protein pilF 0325 200 inner 1 pilus assembly protein PilG pilG 0326 386 inner 8 branched chain amino acid transport system II carrier 0329 395 cytoplasm cystathionine beta-lyase (metC) or trans-sulfuration enzyme family protein 0330 109 cytoplasm sanA protein (sanA) 0333 96 inner 1 folylpolyglutamate synthase/dihydrofolate synthase (folC) 0336 133 cytoplasm short chain dehydrogenase/reductase or oxidoreductase, short-chain dehydrogenase/reductase 0337 391 cytoplasm tryptophan synthase beta subunit (trpB) 0340 151 cytoplasm cell division protein (ftsH) 0342 147 cytoplasm peptide methionine sulfoxide reductase pilB 0346 46 periplasmic small protein A 0347 273 inner 7 transport protein 0349 66 cytoplasm protease 0351 412 inner 1 penicillin-binding protein 1B (ponB) 0352 291 inner 5 carbon starvation protein A cstA 0354 227 cytoplasm GTP pyrophosphokinase (relA) 0355 367 cytoplasm GTP pyrophosphokinase (relA) 0356 65 inner 1 diacylglycerol kinase (dgkA) 0358 56 inner 1 diacylglycerol kinase (dgkA) 0359 275 cytoplasm esterase 0360 216 cytoplasm UDP-3-O-(3-hydroxymyristoyl)-glucosamine N-acyltransferase 0361 141 cytoplasm translation elongation factor Ts (tsf) (EF-TS) 0365 91 cytoplasm exodeoxyribonuclease III (xthA) 0366 432 inner 1 heme-hemopexin utilization protein A (hxuA) 0367 184 cytoplasm carboxy-terminal tail specific protease (prc) 0368 204 cytoplasm carboxy-terminal tail specific protease (prc) 0369 163 cytoplasm dihydroxyacid dehydratase (ilvD) 0370 201 cytoplasm acetohydroxy acid synthase II or acetolactate synthase III, large subunit ilvI 0372 306 inner 7 sodium-dependent transporter or sodium- and chloride-dependent transporter 0373 42 cytoplasm aminotransferase 0374 307 cytoplasm aminotransferase 0376 128 cytoplasm ribosomal protein L17 (rplQ) 0377 193 cytoplasm DNA-directed RNA polymerase, alpha chain (rpoA) 0380 33 cytoplasm acylneuraminate cytidylyltransferase (neuA) 0382 359 cytoplasm peptidyl-prolyl cis-trans isomerse 0386 111 cytoplasm DNA gyrase, subunit A (gyrA) 0387 52 cytoplasm DNA gyrase, subunit A (gyrA) 0388 242 inner 3 sodium/proline symporter (proline permease) (putP) 0391 256 cytoplasm anaerobic ribonucleoside-triphosphate reductase (nrdD) 0392 87 cytoplasm anaerobic ribonucleoside-triphosphate reductase (nrdD) 0393 211 cytoplasm aminotransferase 0394 117 cytoplasm aerobic respiration control protein ARCA (arcA) or DNA-binding response regulator 0397 444 inner 8 thiol:disulfide interchange protein (dsbD) 0399 362 cytoplasm GTP-binding membrane protein (lepA) 0400 437 inner 9 sodium-dependent transporter 0401 206 inner 5 nitrite reductase, transmembrane protein (nrfD) 0402 138 inner 3 cytochrome C-type biogenesis protein or thiol:disulfide interchange protein DsbD dsbD 0403 84 cytoplasm peptide methionine sulfoxide reductase (msrA) 0405 299 periplasmic peptide methionine sulfoxide reductase (msrA) 0418 297 inner 3 cytochrome D ubiquinol oxidase, subunit I (cydA) 0421 287 periplasmic CTP synthetase (pyrG) 0423 385 cytoplasm exodeoxyribonuclease VII, large subunit (xseA) 0425 92 cytoplasm oligopeptide ABC transporter, ATP-binding protein (oppD) 0426 311 inner 6 oligopeptide ABC transporter, permease protein (oppC) 0427 232 inner 6 oligopeptide ABC transporter, permease protein (oppB) or iron(III) ABC transporter, permease protein 0428 316 cytoplasm cysteine synthetase (cysK) 0431 116 cytoplasm C-5 cytosine-specific DNA-methylase 0436 341 cytoplasm peptide chain release factor 3 (prfC) 0437 295 inner 1 enoyl-(acyl-carrier-protein) reductase (fabI) 0441 66 cytoplasm L-2,4-diaminobutyrate decarboxylase 0442 222 cytoplasm formamidopyrimidine-DNA glycosylase (fpg) 0443 160 cytoplasm peptidase T (pepT) 0444 178 inner 0 fuculokinase (fucK) 0447 323 cytoplasm L-fucose isomerase (fucI) 0448 119 cytoplasm L-fucose isomerase (fucI) 0449 193 cytoplasm dethiobiotin synthase (bioD-1) 0451 88 cytoplasm GTP cyclohydrolase I (folE) 0453 113 inner 1 GTP cyclohydrolase I (folE) 0454 78 cytoplasm GTP cyclohydrolase I (folE) 0456 212 cytoplasm protein-PII uridylyl transferase (glnD) 0457 288 inner 9 undecaprenyl-phosphate alpha-N-acetylglucosaminyltransferase or phospho-N-acetylmuramoyl-pentapeptide-transferase 0458 293 cytoplasm penicillin tolerance protein (lytB) 0459 57 inner 1 lipoprotein signal peptidase (lspA) 0460 122 inner 1 lipoprotein signal peptidase (lspA) 0461 433 inner 2 YhbX/YhjW/YijP/YjdB family protein 0462 107 inner 2 transporter protein 0463 159 inner 3 transporter protein 0464 349 cytoplasm 2′,3′-cyclic-nucleotide 2′-phosphodiesterase (cpdB) 0465 73 inner 1 iron (chelated) ABC transporter, permease protein (yfeD) 0467 215 cytoplasm transcriptional activator 0468 314 periplasmic thiamine biosynthesis protein 0469 76 inner 1 ABC transporter, permease protein 0470 328 cytoplasm alanyl-tRNA synthetase (alaS) 0472 122 cytoplasm alanyl-tRNA synthetase (alaS) 0473 89 inner 0 phosphatidylserine decarboxylase proenzyme (psd) 0474 261 cytoplasm glutathione reductase (gor) or 2-oxoglutarate dehydrogenase, E3 component, 0475 241 inner 5 phosphatidylglycerophosphatase B (pgpB) 0476 119 cytoplasm GTP cyclohydrolase II (ribA) 0477 153 cytoplasm DNA polymerase III, delta subunit (holA) 0479 369 cytoplasm glycyl-tRNA synthetase, beta chain (glyS) 0480 305 cytoplasm UDP-3-0-(3-hydroxymyristoyl) N-acetylglucosamine deacetylase 0481 116 cytoplasm chorismate mutase/prephenate dehydratase (pheA) 0483 271 cytoplasm urease accessory protein (ureH) 0490 179 inner 4 glutamate permease (gltS) sodium/glutamate symporter 0492 95 cytoplasm ribosomal protein S6 modification protein (rimK) or glutathione synthetase gshB 0493 123 inner 2 Na+/H+ antiporter (nhaC) 0494 326 cytoplasm xylose operon regluatory protein (xylR) 0495 144 cytoplasm lipopolysaccharide biosynthesis protein or lacto-N-neotetraose biosynthesis glycosyl 0496 257 inner 1 lipopolysaccharide biosynthesis protein 0502 46 outer penicillin-binding protein 7 0503 138 cytoplasm transcription elongation factor (greA) 0504 115 outer D-alanyl-D-alanine 0505 370 cytoplasm D-alanyl-D-alanine or penicillin-binding protein 3 0506 38 cytoplasm IS1016 family transposase 0507 158 inner 1 IS1016-V6 protein (IS1016-V6) 0508 111 cytoplasm IS1016C2 transposase 0514 296 cytoplasm aminopeptidase A/I (pepA) 0515 113 cytoplasm stringent starvation protein B (sspB) 0517 312 cytoplasm 1-deoxyxylulose-5-phosphate synthase (dxs) 0518 150 inner 0 short chain dehydrogenase/reductase 0519 348 cytoplasm phosphoribosylaminoimidazole synthetase (purM) 0521 40 cytoplasm phosphoglycerate mutase (gpmA) 0522 70 cytoplasm ribosomal protein L31 (rpL31) 0524 158 inner 0 A/G-specific adenine glycosylase (mutY) 0525 86 cytoplasm A/G-specific adenine glycosylase (mutY) 0528 170 inner 2 formate dehydrogenase, gamma subunit (fdxI) 0529 319 inner 2 fdhE protein (fdhE) 0530 137 cytoplasm DNA transformation protein (sxy) 0532 571 cytoplasm immunoglobin A1 protease (iga1) or hemagglutinin/hemolysin-related protein 0535 289 cytoplasm threonyl-tRNA synthetase (thrS) 0540 184 cytoplasm competence protein E (comE) 0542 213 cytoplasm competence protein F (comF) 0543 220 cytoplasm hflK protein (hflK) or stomatin/Mec-2 family protein 0544 295 inner 1 hflC protein (hflC) or stomatin/Mec-2 family protein 0547 74 periplasmic sodium/proline symporter (proline permease) (putP) 0548 304 cytoplasm cytoplasmic axial filament protein (cafA) 0549 108 inner 1 cytoplasmic axial filament protein (cafA) 0550 93 cytoplasm cytoplasmic axial filament protein (cafA) 0552 217 cytoplasm cell division protein (mukB) 0554 248 cytoplasm killing protein suppressor (kicA) 0557 245 cytoplasm fdhD protein (fdhD) 0558 38 cytoplasm fdhD protein (fdhD) 0560 30 cytoplasm phosphatidylserine decarboxylase proenzyme (psd) 0563 56 cytoplasm ribosomal protein L32 (rpL32) 0564 225 cytoplasm beta-ketoacyl-ACP synthase III (fabH) or 3-oxoacyl-(acyl-carrier-protein) synthase III fabH 0565 368 inner 7 tryptophan-specific transport protein (mtr) 0566 409 inner 1 L-serine deaminase (sdaA) 0571 292 cytoplasm cytidine deaminase (cdd) 0574 212 inner 2 lipoprotein 0575 65 cytoplasm transcriptional regulator (bolA) 0576 158 cytoplasm NADH:ubiquinone oxidoreducatase subunit A, Na translocating or Na(+)- translocating NADH-quinone reductase, subunit 0580 160 inner 0 translation initiation factor 2 (infB) 0591 200 cytoplasm beta-phosphoglucomutase pgmB 0592 462 cytoplasm cell division protein (mukB) 0594 393 cytoplasm traN-related protein 0595 31 cytoplasm GTP cyclohydrolase II (ribA) 0596 57 cytoplasm GTP cyclohydrolase II (ribA) 0597 345 cytoplasm oligopeptide transporter, periplasmic-binding protein, 0599 32 cytoplasm oligopeptide transporter, periplasmic-binding protein, 0601 240 cytoplasm aminopeptidase P (pepP) 0604 37 cytoplasm aldose 1-epimerase (galM) 0605 195 cytoplasm aldose 1-epimerase (galM) 0607 318 cytoplasm C-5 cytosine-specific DNA-methylase 0608 104 cytoplasm killing protein (kicB) 0609 144 cytoplasm DNA polymerase III, delta subunit (holA) 0611 69 cytoplasm rare lipoprotein B 0613 75 cytoplasm transcriptional regulator (nadR) 0614 310 cytoplasm transcriptional regulator (nadR) 0616 69 cytoplasm aerobic respiration control protein ARCA (arcA) 0618 368 inner 7 sodium/alanine symporter 0619 303 periplasmic elongation factor Tu (tufB) 0622 218 inner 4 dedA protein 0626 164 inner 5 lic-1 operon protein (licB) 0627 321 cytoplasm lic-1 operon protein (licA) 0628 235 cytoplasm UDP-N-acetylenolpyruvoylglucosamine reductase (murB) 0629 179 cytoplasm nitrate/nitrite sensor protein (narQ) 0630 151 inner 1 small major protein B (smpB) 0632 53 cytoplasm 6-phosphofructokinase (pfkA) 0633 290 cytoplasm 6-phosphofructokinase (pfkA) 0635 355 cytoplasm type I modification enzyme (hsdM) 0636 158 inner 2 cysteine synthetase (cysZ) 0638 328 outer cell division protein ZipA 0640 122 cytoplasm ribosomal protein S12 (rps12) 0641 346 cytoplasm glucose inhibited division protein (gidA) 0646 257 inner 5 Na+/H+ antiporter (nhaC) 0647 37 outer Na+/H+ antiporter (nhaC) 0648 362 outer colicin tolerance protein (tolB) 0650 497 cytoplasm cell division protein (mukB) 0651 391 cytoplasm heme-binding lipoprotein (dppA) 0652 78 cytoplasm octaprenyl-diphosphate synthase (ispB) 0654 103 inner 1 ribosomal protein L21 (rpL21) 0655 85 cytoplasm ribosomal protein L27 (rpL27) 0657 83 cytoplasm GTP-binding protein (yhbZ) 0658 75 inner 1 lipopolysaccharide biosynthesis protein 0659 55 cytoplasm lipopolysaccharide biosynthesis protein 0660 255 cytoplasm molybdenum transport protein (modE) 0661 34 periplasmic molybdenum ABC transporter, periplasmic-binding protein 0665 144 cytoplasm single-stranded DNA binding protein (ssb) 0670 366 cytoplasm histidinol-phosphate aminotransferase (hisH) 0671 31 cytoplasm phosphoserine aminotransferase (serC) 0672 31 cytoplasm phosphoserine aminotransferase (serC) 0674 140 cytoplasm ribosomal protein L3 (rpL3) 0675 200 inner 1 ribosomal protein L4 (rpL4) 0676 139 inner 1 ribosomal protein L23 (rpL23) 0679 51 cytoplasm ampD signalling protein (ampD) 0682 96 cytoplasm hemolysin 0684 208 cytoplasm spermidine/putrescine ABC transporter, ATP-binding protein 0685 52 cytoplasm lysyl-tRNA synthetase analog (genX) 0686 227 cytoplasm DNA-binding response regulator (cpxR) 0688 256 cytoplasm aminoacyl-histidine dipeptidase (pepD) 0689 185 cytoplasm integrase/recombinase (xerC) 0698 399 cytoplasm nifS protein 0699 51 cytoplasm nuclease 0701 153 cytoplasm DnaA-related protein 0702 279 inner 7 uracil permease (uraA) 0703 129 inner 3 uracil permease (uraA) 0704 135 cytoplasm uracil phosphoribosyltransferase (upp) 0705 341 cytoplasm glutaminyl-tRNA synthetase (glnS) 0708 78 cytoplasm cytoplasmic axial filament protein (cafA) 0709 258 inner 5 anaerobic C4-dicarboxylate membrane transporter protein 0710 43 inner 1 anaerobic C4-dicarboxylate membrane transporter protein 0714 169 cytoplasm protein-export protein (secB) 0718 175 inner 1 glucose inhibited division protein (gidA) 0719 224 cytoplasm threonyl-tRNA synthetase (thrS) 0720 194 cytoplasm acyl carrier protein phosphodiesterase (acpD) 0723 146 cytoplasm DNA topoisomerase I (topA) 0732 200 cytoplasm recombination protein RecR (recR) 0733 202 cytoplasm DNA topoisomerase III (topB) 0734 322 cytoplasm S-adenosylmethionine synthetase (metX) 0735 193 cytoplasm anthranilate synthase component II (trpG) or para-aminobenzoate synthase glutamine 0736 210 cytoplasm para-aminobenzoate synthetase component 0737 118 cytoplasm folylpolyglutamate synthase/dihydrofolate synthase (folC) 0738 184 periplasmic acetyl-CoA carboxylase, carboxyl transferase subunit beta 0739 93 cytoplasm acetyl-CoA carboxylase, carboxyl transferase subunit beta 0740 177 inner 1 periplasmic serine protease 0741 321 cytoplasm periplasmic serine protease 0743 269 cytoplasm tRNA pseudouridylate synthase I (truA) 0745 235 inner 2 peptide ABC transporter, ATP-binding protein (sapF) 0747 37 cytoplasm peptide ABC transporter, ATP-binding protein (sapF) 0748 44 cytoplasm peptide ABC transporter, ATP-binding protein (sapD) 0751 86 cytoplasm pseudouridine synthase RluD (rluD) 0753 198 cytoplasm tRNA (guanine-N1)-methyltransferase (trmD) 0754 116 cytoplasm ribosomal protein L19 (rpL19) 0758 235 cytoplasm ribosomal protein S3 (rpS3) 0759 110 cytoplasm ribosomal protein L22 (rpL22) 0760 91 cytoplasm ribosomal protein S19 (rpS19) 0761 180 cytoplasm ribosomal protein L2 (rpL2) 0762 221 inner 5 protein-export membrane protein (secD) 0764 406 inner 1 protein-export membrane protein (secD) 0765 97 inner 1 preprotein translocase, YajC subunit (yajC) 0769 37 cytoplasm queuine tRNA-ribosyltransferase (tgt) 0770 371 cytoplasm tRNA 0772 55 cytoplasm thiamine biosynthesis lipoprotein ApbE lipoprotein 0773 35 cytoplasm lipoprotein 0774 299 inner 1 thiamine biosynthesis lipoprotein ApbE lipoprotein 0777 63 cytoplasm ribosomal protein L29 (rpL29) 0778 74 cytoplasm ribosomal protein L16 (rpL16) 0779 335 cytoplasm dihydrolipoamide acetyltransferase (aceF) or pyruvate dehydrogenase, E2 component, 0781 35 cytoplasm dihydrolipoamide acetyltransferase (aceF) 0782 549 cytoplasm pyruvate dehydrogenase, E1 component (aceE) 0787 297 cytoplasm glycine cleavage system transcriptional activator (gcvA) or transcriptional regulator, LysR family 0788 159 outer-hand penicillin-binding protein 1A (ponA) 0790 164 cytoplasm competence protein A (comA) 0794 168 inner 1 competence protein B (comB) 0795 134 inner 1 competence protein C (comC) 0796 172 inner 1 competence protein D (comD) 0798 166 inner 1 competence protein E (comE) 0801 583 cytoplasm arginyl-tRNA synthetase (argS) 0802 100 inner 1 glutaredoxin (grx) 0803 406 inner 0 beta-ketoacyl-ACP synthase I (fabB) 0804 137 inner 1 monofunctional biosynthetic peptidoglycan transglycosylase 0805 101 cytoplasm trp operon repressor (trpR) 0806 305 cytoplasm soluble lytic murein transglycosylase 0807 267 cytoplasm 2-hydroxyacid (glycerate) dehydrogenase 0808 30 cytoplasm 2-dehydro-3-deoxyphosphooctonate aldolase (kdsA) 0810 249 cytoplasm 2-dehydro-3-deoxyphosphooctonate aldolase (kdsA) 0812 84 cytoplasm hemK protein (hemK) 0813 202 inner 1 hemK protein (hemK) 0817 411 cytoplasm hydrolase 0821 240 inner 1 transcriptional regulatory protein (ygiX) 0822 154 inner 1 sensor protein (ygiY) 0823 66 cytoplasm sensor protein (ygiY) 0824 316 cytoplasm glutamyl-tRNA synthetase (gltX) 0825 80 cytoplasm glutamyl-tRNA synthetase (gltX) 0826 79 cytoplasm glutamyl-tRNA synthetase (gltX) 0828 45 cytoplasm ribonuclease PH (rph) 0829 278 inner 1 amidophosphoribosyltransferase (purF) 0830 484 cytoplasm DNA gyrase, subunit A (gyrA) 0831 54 cytoplasm DNA gyrase, subunit A (gyrA) 0833 583 cytoplasm hemin receptor (hemR) or iron-regulated outer membrane protein FrpB frpB 0834 143 inner 2 colicin transport protein (tolQ) or biopolymer transport protein ExbB exbB 0835 139 periplasmic colicin transport protein (tolR) or biopolymer transport protein ExbD exbD 0836 337 inner 1 outer membrane integrity protein (tolA) or IgA-specific serine endopeptidase iga 0840 76 cytoplasm ABC transporter, ATP-binding protein 0842 31 cytoplasm type I restriction enzyme (hsdR) 0844 53 cytoplasm modification methylase 0845 184 cytoplasm ADP-heptose synthase (rfaE) or aut protein aut 0847 389 cytoplasm argininosuccinate lyase (argH) 0848 295 periplasmic glucosephosphate uridylyltransferase (galU) or UTP--glucose-1-phosphate uridylyltransferase galU 0849 63 periplasmic carbon storage regulator (csrA) 0850 461 inner 4 ATP-binding protein protein (cydD) 0851 94 inner 2 ATP-binding protein protein (cydD) 0852 160 inner 1 NAD(P)H oxidoreductase 0856 133 periplasmic protease IV (sppA) 0857 152 cytoplasm molybdenum ABC transporter, periplasmic-binding protein 0858 242 inner 5 molybdenum ABC transporter, permease protein (modB) or sulfate ABC transporter, permease protein cysT 0859 40 cytoplasm molybdenum ABC transporter, ATP-binding protein (modC) 0860 245 cytoplasm molybdenum ABC transporter, ATP-binding protein (modC) or sulfate ABC transporter, ATP-binding protein cysA 0868 119 cytoplasm type I restriction/modification specificity protein (hsdS) 0869 90 cytoplasm anthranilate synthase component I trpE 0873 145 cytoplasm phosphoserine aminotransferase (serC) 0874 234 inner 2 succinyl-CoA synthetase, beta subunit (sucC) 0875 293 inner 1 succinyl-CoA synthetase, alpha subunit (sucD) 0882 93 cytoplasm mazG protein (mazG) 0887 285 inner 1 3-oxoacyl-(acyl-carrier-protein) reductase fabG-2 0890 153 cytoplasm DNA polymerase III, delta′ subunit (holB) 0892 41 cytoplasm thiol:disulfide interchange protein (dsbD) 0893 60 cytoplasm thiol:disulfide interchange protein (dsbD) 0897 234 cytoplasm phosphoribosylaminoimidazolecarboxamide formyltransferase 0898 552 cytoplasm ATP-dependent RNA helicase DeaD (deaD) 0900 64 cytoplasm type I restriction/modification specificity protein (hsdS) 0903 248 cytoplasm type I restriction enzyme (hsdR) 0905 106 cytoplasm 2-isopropylmalate synthase (leuA) 0907 373 cytoplasm DNA processing chain A (dprA) 0910 106 periplasmic nitrite reductase, Fe—S protein (nrfC) 0912 98 cytoplasm nitrite reductase, cytochrome C-type protein (nrfB) 0913 277 inner 1 cell division protein FtsK-related protein 0914 205 outer outer membrane lipoproteins carrier protein (lolA) 0918 286 cytoplasm glycogen phosphorylase (glgP) 0919 323 cytoplasm glycogen phosphorylase (glgP) 0920 117 cytoplasm glycogen phosphorylase (glgP) 0923 253 cytoplasm glycogen synthase (glgA) 0925 105 cytoplasm phosphoglycerate mutase (gpmA) 0934 242 cytoplasm 3-ketoacyl-acyl carrier protein reductase (fabG) 0935 48 cytoplasm malonyl CoA-acyl carrier protein transacylase (fabD) 0936 222 cytoplasm malonyl CoA-acyl carrier protein transacylase (fabD) 0939 111 cytoplasm 3-oxoacyl-(acyl-carrier-protein) synthase III fabH 0945 125 cytoplasm molybdopterin biosynthesis protein (moeB) or thiF protein thiF 0946 404 cytoplasm molybdopterin biosynthesis protein (moeA) 0947 55 cytoplasm GTP cyclohydrolase I (folE) 0950 353 inner 2 protease (sohB) 0954 274 cytoplasm recombination associated protein RdgC rdgC 0956 354 cytoplasm adenosylmethionine-8-amino-7-oxononanoate aminotransferase 0958 379 cytoplasm 8-amino-7-oxononanoate synthase (bioF) 0960 80 cytoplasm ABC transporter, ATP-binding protein 0962 66 cytoplasm ABC transporter, ATP-binding protein 0963 317 cytoplasm ABC transporter, ATP-binding protein (msbA) 0965 313 cytoplasm tetraacyldisaccharide 4′-kinase lpxK 0966 254 cytoplasm 3-deoxy-D-manno-octulosonate cytidylyltransferase (kdsB) 0967 77 cytoplasm excinuclease ABC, subunit C (uvrC) 0969 204 cytoplasm ABC transporter, ATP-binding protein 0974 90 cytoplasm dethiobiotin synthase (bioD-2) 0976 223 cytoplasm biotin synthesis protein BioC 0977 549 cytoplasm long chain fatty acid coA ligase 0983 574 cytoplasm phosphoenolpyruvate carboxylase (ppc) 0984 303 cytoplasm gcpE protein (gcpE) 0988 226 cytoplasm rbs repressor (rbsR) 0989 322 inner 1 ribokinase (rbsK) or ADP-heptose synthase 0990 156 cytoplasm D-ribose ABC transporter, periplasmic-binding protein (rbsB) 0992 223 cytoplasm baseplate assembly protein V 0994 52 inner 0 adhesin/invasin 0997 454 lipo multidrug efflux pump channel protein mtrE 1001 273 cytoplasm transcription termination factor (rho) 1002 230 inner 5 type 4 prepilin-like protein specific leader peptidase 1003 143 inner 1 pilus assembly protein PilG pilG 1007 39 cytoplasm glycerol-3-phosphate regulon repressor (glpR) 1008 306 cytoplasm fructose-1,6-bisphosphatase (fbp) 1012 233 inner 8 hydroxyacylglutathione hydrolase 1014 182 cytoplasm tellurite resistance protein (tehB) 1015 541 periplasmic oligopeptide ABC transporter, periplasmic-binding protein 1018 45 periplasmic oligopeptide ABC transporter, permease protein (oppB) 1019 256 cytoplasm methylenetetrahydrofolate 1021 428 inner 0 L-fucose permease (fucP) or glucose/galactose transporter gluP 1022 216 cytoplasm L-fuculose phosphate aldolase (fucA) 1023 144 cytoplasm fucose operon protein (fucU) 1024 30 cytoplasm fuculokinase (fucK) 1030 492 cytoplasm anaerobic glycerol-3-phosphate dehydrogenase, subunit A 1031 320 inner 1 anaerobic glycerol-3-phosphate dehydrogenase, subunit B 1032 242 inner 5 transporter 1033 116 cytoplasm arsenate reductase 1041 70 cytoplasm hypoxanthine phosphoribosyltransferase (hpt) 1043 460 inner 9 proton glutamate symport protein or sodium/dicarboxylate symporter family protein 1045 155 cytoplasm anaerobic ribonucleoside-triphosphate reductase activating 1046 242 cytoplasm transport ATP-binding protein (cydC) ABC transporter 1048 212 inner 4 transport ATP-binding protein (cydC) 1050 359 cytoplasm fructose-bisphosphate aldolase (fba) 1051 346 cytoplasm ADP-heptose--LPS heptosyltransferase II rfaF 1053 56 cytoplasm peptidyl-prolyl cis-trans isomerse 1054 201 outer peptidyl-prolyl cis-trans isomerse 1057 452 cytoplasm thiophene and furan oxidation protein (thdF) 1058 224 inner 2 inner membrane protein, 60 kDa (yidC) 1059 58 cytoplasm ribosomal protein S18 (rpS18) 1060 149 cytoplasm ribosomal protein L9 (rpL9) 1061 577 cytoplasm heat shock protein (groEL) 1062 102 cytoplasm chaperonin (groES) 1063 190 inner 4 urease, gamma subunit (ureA) 1064 216 inner 5 rod shape-determining protein (rodA) or cell division protein FtsW ftsW 1066 66 cytoplasm penicillin-binding protein 2 (pbp2) 1068 66 cytoplasm cell division protein FtsK-related protein 1071 447 cytoplasm protease IV (sppA) 1074 286 cytoplasm lic-1 operon protein (licD) 1075 213 outer aminopeptidase A/I (pepA) 1077 141 cytoplasm nucleoside diphosphate kinase (ndk) 1078 227 cytoplasm GTP-binding protein (yhbZ) 1080 317 inner 1 phosphoribosylamine--glycine ligase (purD) 1081 198 cytoplasm phosphoribosylaminoimidazolecarboxamide formyltransferase 1082 31 outer phosphoribosylaminoimidazolecarboxamide formyltransferase 1083 45 inner 0 phosphoribosylaminoimidazolecarboxamide formyltransferase 1084 199 inner 0 sufI protein (sufI) 1085 125 inner 1 1-acyl-glycerol-3-phosphate acyltransferase (plsC) 1087 75 inner 1 1-acyl-glycerol-3-phosphate acyltransferase (plsC) 1091 199 inner 4 sodium- and chloride-dependent transporter 1092 217 inner 2 potassium/copper-transporting ATPase 1093 68 cytoplasm mercuric ion scavenger protein (merP) 1094 68 cytoplasm mercuric ion scavenger protein (merP) 1095 68 cytoplasm mercuric ion scavenger protein (merP) 1096 144 cytoplasm transcriptional regulator, merR family 1097 105 cytoplasm met repressor (metJ) 1098 109 inner 1 transcription termination factor (rho) 1100 317 cytoplasm fumarate reductase, flavoprotein subunit (frdA) or succinate dehydrogenase, flavoprotein subunit sdhA 1101 276 cytoplasm fumarate reductase, iron-sulfur protein (frdB) or succinate dehydrogenase, iron-sulfur protein sdhB 1102 132 inner 3 fumarate reductase, 15 kDa hydrophobic protein (frdC) 1103 114 inner 1 fumarate reductase, 13 kDa hydrophobic protein (frdD) 1109 170 cytoplasm terminase, small subunit 1116 51 cytoplasm heme-hemopexin utilization protein A (hxuA) 1117 165 cytoplasm heme-hemopexin utilization protein A (hxuA) 1120 118 cytoplasm dihydroneopterin aldolase (folB) 1124 338 inner 1 nitrate/nitrite sensor protein (narQ) 1125 225 inner 1 topoisomerase IV, subunit A (parC) 1127 139 cytoplasm glucose kinase 1132 202 cytoplasm type I modification enzyme (hsdM) 1135 260 cytoplasm type I modification enzyme (hsdM) 1137 362 cytoplasm type I restriction/modification specificity protein (hsdS) 1138 226 inner 0 thiamin-phosphate pyrophosphorylase 1139 254 cytoplasm phosphomethylpyrimidine kinase (thiD) 1140 32 cytoplasm phosphomethylpyrimidine kinase (thiD) 1141 263 inner 1 hydroxyethylthiazole kinase 1143 70 cytoplasm outer membrane protein NsgA 1144 51 cytoplasm ribonuclease E (rne) 1145 75 cytoplasm ribonuclease E (rne) 1148 42 cytoplasm ribonuclease E (rne) 1151 180 inner 1 adenine phosphoribosyltransferase (apt) 1152 311 cytoplasm DNA polymerase III, subunits gamma and tau (dnaX) 1154 221 cytoplasm DNA polymerase III, subunits gamma and tau (dnaX) 1155 173 cytoplasm DNA polymerase III, subunits gamma and tau (dnaX) 1156 60 cytoplasm uracil phosphoribosyltransferase (upp) 1165 406 cytoplasm nifS protein (nifS) 1166 151 cytoplasm iscU protein (iscU) 1167 107 cytoplasm HesB/YadR/YfhF family protein 1168 174 cytoplasm co-chaperone Hsc20 (hscB) 1171 151 cytoplasm heat shock protein (hscA) 1172 53 cytoplasm D-lactate dehydrogenase (dld) 1173 36 cytoplasm type I restriction enzyme EcoR124II R protein, 1174 183 lipo lipoprotein (spr) 1175 194 cytoplasm tldD protein tldD 1177 44 cytoplasm hemoglobin-binding protein 1180 234 cytoplasm peptidase E (pepE) 1182 386 cytoplasm ribosomal protein S1 (rpS1) 1183 94 cytoplasm integration host factor, beta-subunit (himD) 1186 194 cytoplasm orotidine 5′-phosphate decarboxylase (pyrF) 1188 181 inner 1 lipopolysaccharide biosynthesis protein 1189 264 inner 1 alpha-1,2-N-acetylglucosamine transferase rfaK 1190 57 periplasmic lipopolysaccharide biosynthesis protein 1191 304 inner 2 alpha-2,3-sialyltransferase 1192 160 inner 4 lipopolysaccharide biosynthesis protein 1197 124 cytoplasm uridine kinase (udk) 1198 195 cytoplasm deoxycytidine triphosphate deaminase (dcd) 1201 402 inner 10 drug resistance translocase family protein 1202 158 cytoplasm GTP-binding protein 1203 55 outer hemoglobin-binding protein 1206 736 cytoplasm TonB-dependent receptor or hemoglobin receptor hmbR 1207 91 cytoplasm transcriptional regulator, HTH_3 family 1212 230 cytoplasm glycyl-tRNA synthetase, beta chain (glyS) 1218 244 cytoplasm glycyl-tRNA synthetase, alpha chain (glyQ) 1228 198 cytoplasm seryl-tRNA synthetase (serS) 1229 282 inner 2 cytochrome C-type biogenesis protein (nrfF) 1230 176 inner 1 thiol:disulfide interchange protein (dsbE) 1231 507 inner 9 cytochrome C-type biogenesis 1233 380 inner 1 glutamate dehydrogenase (gdhA) 1242 135 cytoplasm transcriptional regulator 1253 266 cytoplasm transcriptional regulatory protein 1254 101 inner 3 galactoside ABC transporter, permease protein (mglC) 1256 185 inner 6 intracellular septation protein A ispA 1258 154 cytoplasm acyl CoA thioester hydrolase family protein 1261 158 periplasmic soluble lytic murein transglycosylase 1263 229 cytoplasm pyridoxamine phosphate oxidase (pdxH) 1264 162 cytoplasm GTP-binding protein 1266 69 cytoplasm NAD(P)H-flavin oxidoreductase 1267 386 cytoplasm ATP-binding protein (mrp) 1268 460 periplasmic methionyl-tRNA synthetase (metG) 1269 70 cytoplasm phosphoribosylaminoimidazole carboxylase, catalytic 1272 596 cytoplasm aminopeptidase N (pepN) 1273 175 inner 1 dihydrodipicolinate reductase (dapB) 1274 82 cytoplasm ferredoxin 1276 329 cytoplasm phenylalanyl-tRNA synthetase, alpha subunit (pheS) 1277 373 cytoplasm phenylalanyl-tRNA synthetase, beta subunit (pheT) 1278 286 cytoplasm DNA adenine methylase (dam) 1279 298 inner 1 3-dehydroquinate synthase (aroB) 1280 74 inner 2 NADH:ubiquinone oxidoreductase, Na translocating 1281 208 inner 6 NADH:ubiquinone oxidoreductase, Na translocating 1282 269 inner 1 NADH:ubiquinone oxidoreductase, Na translocating 1283 411 inner 7 NADH:ubiquinone oxidoreductase, subunit B (nqrB) 1284 48 cytoplasm NADH:ubiquinone oxidoreducatase subunit A, Na translocating 1285 254 cytoplasm NADH:ubiquinone oxidoreducatase subunit A, Na translocating 1286 85 inner 1 nitrogen fixation protein (rnfG) 1287 358 inner 9 Na(+)-translocating NADH-quinone reductase, subunit 1290 679 outer ferredoxin, 4Fe—4S bacterial type 1291 58 cytoplasm ferredoxin, 4Fe—4S bacterial type 1295 406 inner 1 polyribonucleotide nucleotidyltransferase pnp 1297 296 inner 1 polyribonucleotide nucleotidyltransferase pnp 1302 452 inner 1 O-succinylbenzoate--CoA ligase (menE) or long-chain-fatty-acid--CoA ligase fadD-2 1303 201 cytoplasm seqA protein (seqA) 1304 85 cytoplasm esterase/lipase 1305 65 inner 1 esterase/lipase 1306 144 inner 0 esterase/lipase 1307 41 inner 1 iron (chelated) ABC transporter, permease protein (yfeD) 1308 147 inner 2 iron (chelated) ABC transporter, permease protein (yfeD) 1309 282 inner 8 iron (chelated) ABC transporter, permease protein (yfeC) 1310 306 cytoplasm iron (chelated) transporter, ATP-binding protein (yfeB) 1311 293 periplasmic iron (chelated) ABC transporter, periplasmic-binding protein 1313 154 lipo outer membrane integrity protein (tolA) or IgA-specific serine endopeptidase iga 1314 253 cytoplasm penicillin-binding protein 7 1318 41 cytoplasm transcriptional activator (ilvY) 1319 292 inner 9 rarD protein 1320 105 cytoplasm glpE protein (glpE) 1321 263 inner 1 triosephosphate isomerase (tpiA) 1323 107 cytoplasm integrase/recombinase (xerC) 1324 100 cytoplasm dnaK suppressor protein (dksA) 1326 58 cytoplasm poly(A) polymerase (pcnB) 1327 450 inner 10 C4-dicarboxylate transporter 1331 131 cytoplasm uracil DNA glycosylase (ung) 1332 124 inner 2 bicyclomycin resistance protein (bcr) 1338 50 cytoplasm gamma-glutamyl phosphate reductase (proA) 1339 47 cytoplasm gamma-glutamyl phosphate reductase (proA) 1340 39 cytoplasm gamma-glutamyl phosphate reductase (proA) 1341 319 inner 1 gamma-glutamyl phosphate reductase (proA) 1343 98 cytoplasm heat shock protein (dnaJ) 1344 133 cytoplasm acetyl-CoA carboxylase, biotin carboxyl carrier protein 1345 443 cytoplasm acetyl-CoA carboxylase, biotin carboxylase (accC) 1348 320 inner 7 sodium/pantothenate symporter (panF) 1349 493 cytoplasm cell division protein (ftsH) 1351 201 cytoplasm dihydropteroate synthase (folP-2) 1352 445 cytoplasm mrsA protein (mrsA) or phosphoglucomutase/phosphomannomutase family 1355 438 cytoplasm DNA-directed RNA polymerase, beta′ chain (rpoC) 1357 172 inner 2 rod shape-determining protein (rodA) 1359 621 inner 1 penicillin-binding protein 2 (pbp2) 1361 193 cytoplasm modification methylase NlaIV 1363 432 inner 1 3-phosphoshikimate-1-carboxyvinyltransferase (aroA) or 3- 1365 298 inner 1 formyltetrahydrofolate deformylase (purU) or phosphoribosylglycinamide formyltransferase purN 1366 138 cytoplasm DNA-binding protein H-NS (hns) 1369 66 cytoplasm DNA polymerase III, alpha subunit (dnaE) 1370 35 cytoplasm DNA polymerase III, alpha subunit (dnaE) 1371 847 cytoplasm DNA polymerase III, alpha subunit (dnaE) 1373 118 cytoplasm threonine deaminase (ilvA) 1378 196 cytoplasm MutT/nudix family protein 1379 382 inner 1 glutamate 5-kinase (gamma-glutamyl kinase) (proB) 1380 128 inner 0 dihydrofolate reductase (folA) 1381 46 cytoplasm dihydrofolate reductase (folA) 1383 392 inner 2 multidrug resistance protein A (emrA) or fatty acid efflux system protein farA 1384 343 cytoplasm poly(A) polymerase (pcnB) 1386 106 cytoplasm 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine- 1388 432 periplasmic N-acetylmuramoyl-L-alanine amidase 1389 227 cytoplasm DNA mismatch repair protein (mutL) 1392 247 cytoplasm hemY protein (hemY) 1393 175 inner 1 hemY protein (hemY) 1394 377 periplasmic uroporphyrin-III C-methyltransferase (hemX) 1398 194 inner 0 transcriptional activator (ilvY) 1400 492 inner 1 ketol-acid reductoisomerase (ilvC) 1401 426 cytoplasm anaerobic glycerol-3-phosphate dehydrogenase, subunit C 1402 30 cytoplasm tRNA (guanine-N1)-methyltransferase (trmD) 1403 59 cytoplasm 16S rRNA processing protein RimM rimM 1404 81 cytoplasm 16S rRNA processing protein RimM rimM 1405 82 cytoplasm ribosomal protein S16 (rpS16) 1407 603 periplasmic 5′-nucleotidase 1408 128 cytoplasm shikimic acid kinase I (aroK) 1410 249 cytoplasm stationary-phase survival protein (surE) 1411 128 inner 2 lipoprotein B (lppB) 1412 74 inner 1 lipoprotein B (lppB) 1416 354 lipo lipoprotein NlpD 1417 56 cytoplasm lipoprotein NlpD 1420 62 inner 1 phosphate ABC transporter, permease protein (pstC) 1421 282 inner 5 phosphate ABC transporter, permease protein (pstA) or sulfate ABC transporter, permease protein cysT 1422 255 cytoplasm amino acid ABC transporter, ATP-binding protein or sulfate ABC transporter, ATP-binding protein cysA 1423 154 cytoplasm phosphate regulon transcriptional regulatory protein (phoB) or DNA-binding response regulator NULL 1424 72 cytoplasm phosphate regulon transcriptional regulatory protein (phoB) 1425 425 inner 1 phosphate regulon sensor protein (phoR) or sensor histidine kinase NULL 1426 44 cytoplasm exodeoxyribonuclease I (sbcB) 1427 474 inner 1 exodeoxyribonuclease I (sbcB) 1428 158 inner 1 aminopeptidase A/I (pepA) 1429 480 inner 5 high-affinity choline transport protein (betT) 1430 132 inner 2 high-affinity choline transport protein (betT) 1431 57 inner 0 sensor protein (ygiY) 1432 139 cytoplasm high affinity ribose transport protein (rbsD) 1433 493 cytoplasm D-ribose ABC transporter, ATP-binding protein (rbsA) 1434 323 inner 9 D-ribose ABC transporter, permease protein (rbsC) 1435 53 periplasmic D-ribose ABC transporter, periplasmic-binding protein 1436 88 cytoplasm D-ribose ABC transporter, periplasmic-binding protein (rbsB) 1438 246 inner 6 heme exporter protein C (ccmC) or cytochrome c-type biogenesis protein 1439 221 inner 6 heme exporter protein B (ccmB) 1440 212 cytoplasm heme exporter ATP-binding protein A (ccmA) or amino acid ABC transporter, ATP-binding protein 1442 215 cytoplasm superoxide dismutase (sodA) 1443 231 cytoplasm ABC transporter, ATP-binding protein 1445 105 cytoplasm anti-sigma factor B antagonist 1446 99 cytoplasm BolA/YrbA family protein 1447 424 inner 3 UDP-N-acetylglucosamine 1-carboxyvinyltransferase (murZ) 1448 110 inner 1 amino acid ABC transporter, periplasmic-binding protein 1449 135 cytoplasm amino acid ABC transporter, periplasmic-binding protein 1450 234 inner 3 amino acid ABC transporter, permease protein 1456 51 cytoplasm ATP-dependent Clp protease, ATPase subunit (clpB) 1457 246 cytoplasm RNA methyltransferase, TrmH family 1459 782 cytoplasm virulence-associated protein (vacB) or ribonuclease II family protein vacB 1460 83 cytoplasm peptidyl-prolyl cis-trans isomerase, FkbP-type (slyD) or FKBP-type peptidyl- prolyl cis-trans isomerase 1462 128 cytoplasm ribosome binding factor A (rbfA) 1463 306 cytoplasm tRNA pseudouridine 55 synthase (truB) 1464 379 inner 1 chorismate mutase/prephenate dehydrogenase (tyrA) 1467 38 inner 1 chorismate synthase (aroC) 1468 286 periplasmic penicillin-insensitive murein endopeptidase (mepA) 1472 318 inner 2 lipid A biosynthesis (kdo)2-(lauroyl)-lipid IVA or HtrB/MsbB family protein 1473 126 inner 1 oligopeptide transporter, periplasmic-binding protein, 1475 696 cytoplasm oligopeptidase A (prlC) 1476 292 cytoplasm type I modification enzyme (hsdM) 1477 196 cytoplasm type I modification enzyme (hsdM) 1480 204 cytoplasm riboflavin synthase, alpha chain (ribE) 1482 212 cytoplasm aminopeptidase N (pepN) 1483 140 cytoplasm glutaminyl-tRNA synthetase (glnS) 1485 699 cytoplasm 4-alpha-glucanotransferase (malQ) 1499 273 cytoplasm glutamine synthetase (glnA) 1500 96 inner 1 glutamine synthetase (glnA) 1501 50 cytoplasm glutamine synthetase (glnA) 1503 347 inner 0 DTDP-glucose 4,6-dehydratase (rffG) 1505 527 cytoplasm topoisomerase IV, subunit B (parE) 1506 315 inner 1 lipid A biosynthesis lauroyl acyltransferase (htrB) 1507 308 cytoplasm ADP-heptose synthase (rfaE) 1508 83 cytoplasm DNA-directed RNA polymerase, beta′ chain (rpoC) 1509 829 cytoplasm DNA-directed RNA polymerase, beta′ chain (rpoC) 1510 332 inner 8 tellurite resistance protein (tehA) 1511 81 cytoplasm ribosomal protein L13 (rpL13) 1512 153 cytoplasm ribosomal protein S9 (rpS9) 1513 101 cytoplasm urease, beta subunit (ureB) 1514 572 cytoplasm urease, alpha subunit (ureC) 1515 185 inner 1 urease accessory protein (ureE) 1519 183 cytoplasm urease accessory protein (ureF) 1520 107 cytoplasm urease accessory protein (ureG) 1523 334 cytoplasm ornithine carbamoyltransferase (arcB) 1524 310 cytoplasm carbamate kinase (arcC) 1526 193 inner 3 efflux pump component MtrF mtrF 1527 113 inner 2 anaerobic C4-dicarboxylate membrane transporter protein 1528 136 inner 1 NADH dehydrogenase (ndh) 1530 315 cytoplasm NADH dehydrogenase (ndh) 1531 410 inner 1 glycerol-3-phosphate acyltransferase (plsB) 1532 367 inner 0 glycerol-3-phosphate acyltransferase (plsB) 1533 75 cytoplasm lexA repressor (lexA) 1534 121 cytoplasm opacity protein or outer membrane protein NsgA nsgA 1537 227 inner 4 arginine ABC transporter, permease protein (artM) 1538 221 inner 4 arginine ABC transporter, permease protein (artQ) 1539 72 cytoplasm arginine ABC transporter, periplasmic-binding protein (artI) 1541 99 periplasmic arginine ABC transporter, periplasmic-binding protein 1542 243 cytoplasm arginine ABC transporter, ATP-binding protein (artP) 1544 69 cytoplasm phosphoheptose isomerase (gmhA) 1545 73 cytoplasm shikimate 5-dehydrogenase-related protein 1546 267 cytoplasm serine acetyltransferase (cysE) 1548 332 inner 1 glycerol-3-phosphate dehydrogenase (NAD+) (gpsA) 1549 567 cytoplasm adenylate cyclase (cyaA) 1550 42 cytoplasm adenylate cyclase (cyaA) 1551 228 cytoplasm adenylate cyclase (cyaA) 1552 110 lipo ribosomal-protein-alanine acetyltransferase (rimI) 1554 134 cytoplasm DNA polymerase III, psi subunit (holD) 1556 222 cytoplasm hemK protein hemK 1558 181 cytoplasm GTP-binding protein (era) 1559 125 inner 0 GTP-binding protein (era) 1561 227 cytoplasm ribonuclease III (rnc) 1562 349 inner 3 signal peptidase I (lepB) 1565 345 cytoplasm tail fibre protein 1568 395 cytoplasm tyrosyl tRNA synthetase (tyrS) 1569 315 inner 1 phosphoribosylpyrophosphate synthetase (prsA) 1575 72 inner 1 IS1016-V6 protein 1576 563 cytoplasm glucose-6-phosphate isomerase (pgi) 1577 360 cytoplasm alanine racemase, biosynthetic (alr) 1578 126 cytoplasm replicative DNA helicase (dnaB) 1579 303 cytoplasm replicative DNA helicase (dnaB) 1582 991 outer-hand hemoglobin-binding protein 1583 237 cytoplasm zinc protease 1584 276 inner 1 adenylosuccinate synthetase (purA) 1585 41 cytoplasm adenylosuccinate synthetase (purA) 1586 297 inner 1 2,3,4,5-tetrahydropyridine-2-carboxylate 1588 336 inner 1 purine nucleotide synthesis repressor (purR) 1589 78 cytoplasm phosphoenolpyruvate carboxylase (ppc) 1590 45 inner 1 ribosomal protein S1 (rpS1) 1591 244 cytoplasm cytidylate kinase 2 (cmkB) 1593 291 cytoplasm singlet oxygen resistance protein 1597 549 inner 1 D-lactate dehydrogenase (dld) 1609 462 inner 1 oxidoreductase 1610 199 cytoplasm spermidine/putrescine ABC transporter, periplasmic-binding 1613 41 cytoplasm carbonic anhydrase 1614 647 cytoplasm ABC transporter, ATP-binding protein 1618 289 inner 6 cytochrome C-type biogenesis protein (ccmF) 1619 181 periplasmic thiol:disulfide interchange protein (dsbE) 1624 152 cytoplasm DNA ligase (lig) 1625 1027 inner 1 type I restriction enzyme (hsdR) 1627 123 cytoplasm anticodon nuclease prrC 1629 177 inner 1 oligopeptide ABC transporter, ATP-binding protein (oppD) or sulfate ABC transporter, ATP-binding protein cysA 1630 356 cytoplasm oligopeptide ABC transporter, ATP-binding protein (oppF) or sulfate ABC transporter, ATP-binding protein cysA 1631 292 inner 1 membrane protein (lapB) 1635 683 cytoplasm 5-methyltetrahydropteroyltriglutamate-homocysteine 1636 73 cytoplasm 5-methyltetrahydropteroyltriglutamate-homocysteine 1639 363 cytoplasm GTP-binding protein 1640 194 cytoplasm peptidyl-tRNA hydrolase (pth) 1645 163 cytoplasm exodeoxyribonuclease VII, large subunit (xseA) 1646 183 cytoplasm YhbX/YhjW/YijP/YjdB family protein 1648 242 cytoplasm heat shock protein (dnaJ) 1650 320 cytoplasm heat shock protein 70 (dnaK) 1651 327 cytoplasm heat shock protein 70 (dnaK) 1653 411 inner 8 gluconate permease gntP 1659 269 cytoplasm molybdenum cofactor biosynthesis protein A (moaA) 1662 337 inner 2 sugar isomerase, KpsF/GutQ family 1664 531 inner 1 single-stranded-DNA-specific exonuclease (recJ) 1665 39 cytoplasm single-stranded-DNA-specific exonuclease (recJ) 1666 235 outer thiol:disulfide interchange protein (dsbA) 1668 230 inner 1 pfs protein (pfs) or 5-methylthioadenosine 1670 565 cytoplasm transferrin-binding protein or TonB-dependent receptor 1671 568 inner 1 lon protease or ATP-dependent protease La lon 1672 139 cytoplasm 3-hydroxydecanoyl-(acyl carrier-protein) dehydratase (fabA) 1678 155 cytoplasm bacterioferritin comigratory protein (bcp) 1679 286 cytoplasm dihydrodipicolinate synthetase (dapA) 1680 209 lipo lipoprotein 1681 107 cytoplasm sigma(54) modulation protein 1682 312 cytoplasm glycosyl transferase 1688 613 inner 2 sensor histidine kinase 1690 145 inner 1 UDP-N-acetylglucosamine acetyltransferase (lpxA) 1692 403 inner 0 lipid-A-disaccharide synthetase (lpxB) 1693 197 inner 1 ribonuclease HII (rnhB) 1694 146 cytoplasm modification methylase 1696 185 cytoplasm ribosome releasing factor (rrf) 1698 226 inner 1 1-deoxy-D-xylulose 5-phosphate reductoisomerase (dxr) 1700 171 cytoplasm 1-deoxy-D-xylulose 5-phosphate reductoisomerase (dxr) 1704 370 cytoplasm ribonucleoside-diphosphate reductase, alpha chain (nrdA) 1705 39 cytoplasm ribonucleoside diphosphate reductase, beta chain (nrdB) 1706 311 cytoplasm ribonucleoside diphosphate reductase, beta chain (nrdB) 1707 409 inner 1 2-oxoglutarate dehydrogenase E2 component, dihydrolipoamide 1708 222 cytoplasm 2-oxoglutarate dehydrogenase E1 component (sucA) 1709 184 cytoplasm ribosomal protein S4 (rpS4) 1712 314 inner 2 phosphoserine phosphatase (serB) 1714 680 cytoplasm transketolase 1 (tktA) 1716 333 cytoplasm biotin synthetase (bioB) 1717 217 cytoplasm thiamin ABC transporter, ATP-binding protein or spermidine/putrescine ABC transporter, ATP-binding 1718 84 inner 1 thiamin ABC transporter, permease protein 1719 77 inner 1 molybdopeterin biosynthesis protein (mog) 1720 112 cytoplasm nitrogen regulatory protein P-II (glnB) 1722 348 inner 6 transporter 1724 264 periplasmic primosomal protein N′ (priA) 1725 487 inner 1 primosomal protein N′ (priA) 1726 102 cytoplasm PTS system, glucose-specific IIA component (crr) 1729 581 inner 1 phosphoenolpyruvate-protein phosphotransferase (ptsI) 1730 92 cytoplasm phosphocarrier protein HPr (ptsH) 1733 189 cytoplasm oligoribonuclease orn 1735 294 inner 2 phenylalanyl-tRNA synthetase, beta subunit (pheT) 1736 53 cytoplasm integration host factor, alpha-subunit (himA) 1738 47 cytoplasm integration host factor, alpha-subunit (himA) 1739 161 lipo lipoprotein (nlpC) 1747 87 cytoplasm pyruvate kinase, type II (pykA) 1758 387 cytoplasm modification methylase NlaIV 1766 90 cytoplasm exodeoxyribonuclease, small subunit (xseB) 1767 296 inner 1 geranyltranstransferase (ispA) 1768 316 cytoplasm 1-deoxyxylulose-5-phosphate synthase (dxs) 1770 99 inner 1 glycosyl transferase 1771 464 cytoplasm fumarate hydratase, class II (fumC) 1776 315 cytoplasm dihydroorotate dehydrogenase (pyrD) 1780 669 cytoplasm transferrin-binding protein 2 precursor (tbp2) 1781 560 periplasmic transferrin-binding protein 1 precursor (tbp1) 1782 152 inner 1 deoxyuridinetriphosphatase (dut) 1783 400 inner 1 DNA/pantothenate metabolism flavoprotein (dfp) 1785 234 cytoplasm DNA repair protein (radC) 1786 82 cytoplasm ribosomal protein L28 (rpL28) 1787 56 cytoplasm ribosomal protein L33 (rpL33) 1788 454 inner 1 L-2,4-diaminobutyrate:2-ketoglutarate 4-aminotransferase or acetylornithine aminotransferase argD 1790 132 cytoplasm virulence associated protein C (vapC) 1791 443 cytoplasm L-2,4-diaminobutyrate decarboxylase 1792 434 cytoplasm ATP-dependent RNA helicase (hrpa) 1793 780 inner 1 ATP-dependent RNA helicase (hrpa) 1794 122 cytoplasm ATP-dependent helicase (hrpa) 1799 243 inner 5 cytochrome D ubiquinol oxidase, subunit II (cydB) 1800 198 cytoplasm uxu operon regulator (uxuR) 1801 51 cytoplasm mannonate dehydratase (uxuA) 1802 33 cytoplasm acyl carrier protein (acpP) 1803 220 inner 5 anaerobic C4-dicarboxylate membrane transporter protein 1805 486 inner 5 NAD(P) transhydrogenase, subunit alpha (pntA) 1806 474 inner 7 NAD(P) transhydrogenase, subunit beta (pntB) 1807 305 periplasmic transcriptional regulator 1808 70 cytoplasm DNA topoisomerase I (topA) 1809 50 cytoplasm signal recognition particle protein (ffh) 1812 88 cytoplasm type I restriction enzyme (hsdR) 1813 646 inner 1 type I restriction enzyme (hsdR) 1815 418 inner 1 type I restriction/modification specificity protein (hsdS) 1819 545 outer heme-hemopexin utilization protein B (hxuB) 1825 402 cytoplasm xylose isomerase (xylA) 1826 493 cytoplasm xylulose kinase 1827 308 cytoplasm ADP-L-glycero-D-mannoheptose-6-epimerase (rfaD) 1828 167 inner 1 thioredoxin 1830 223 cytoplasm deoxyribose-phosphate aldolase (deoC) 1831 509 cytoplasm competence protein (comM) 1834 72 cytoplasm glucose kinase 1835 288 inner 1 RpiR/YebK/YfhH family protein 1836 293 inner 0 N-acetylneuraminate lyase (nanA) or dihydrodipicolinate synthase dapA 1838 270 cytoplasm glucosamine-6-phosphate isomerase (nagB) 1839 381 cytoplasm N-acetylglucosamine-6-phosphate deacetylase (nagA) 1840 107 cytoplasm outer membrane protein P2 (ompP2) 1841 38 cytoplasm DNA polymerase III, delta′ subunit (holB) 1845 716 outer-hand LavA virulence protein 1846 237 cytoplasm thymidylate kinase 1848 265 cytoplasm argininosuccinate synthetase (argG) 1855 97 cytoplasm exoribonuclease II (rnb) 1858 188 cytoplasm L-lactate dehydrogenase (lctD) 1859 269 inner 1 glutamate racemase (murI) 1860 693 cytoplasm ATP-dependent DNA helicase (recG) 1861 515 inner 1 guanosine-3′,5′-bis(diphosphate) 3′-pyrophosphohydrolase 1867 69 cytoplasm molybdenum-pterin binding protein (mopI) 1868 109 cytoplasm desulfoviridin gamma subunit 1870 393 inner 1 killing protein (kicB) 1871 343 periplasmic enolase (eno) 1875 508 cytoplasm catalase (hktE) 1876 50 cytoplasm glucosamine--fructose-6-phosphate aminotransferase (glmS) 1877 232 cytoplasm glycogen synthase (glgA) 1879 174 cytoplasm glucose-1-phosphate adenylyltransferase (glgC) 1880 283 cytoplasm glucose-1-phosphate adenylyltransferase (glgC) 1881 435 inner 1 glycogen operon protein (glgX) 1882 229 inner 1 glycogen operon protein (glgX) 1883 685 cytoplasm 1,4-alpha-glucan branching enzyme (glgB) 1884 119 cytoplasm ribosomal protein S10 (rpS10) 1885 315 inner 1 cys regulon transcriptional activator cysB 1886 217 cytoplasm acetate CoA-transferase, alpha subunit 1887 233 cytoplasm acetate CoA-transferase, beta subunit (atoA) 1888 344 inner 5 short-chain fatty acids transporter (atoE) 1889 84 inner 1 short-chain fatty acids transporter (atoE) 1890 393 cytoplasm acetyl-CoA acetyltransferase (atoB) 1891 310 inner 4 cell division protein (ftsX) 1892 119 periplasmic cell division ATP-binding protein (ftsE) 1893 129 cytoplasm cell division ATP-binding protein (ftsE) 1894 175 cytoplasm signal recognition particle-docking protein FtsY (ftsY) 1895 243 cytoplasm peptide ABC transporter, ATP-binding protein (sapD) 1896 105 inner 2 peptide ABC transporter, permease protein (sapC) 1897 50 periplasmic peptide ABC transporter, permease protein (sapC) 1898 184 inner 4 peptide ABC transporter, permease protein (sapC) 1899 321 inner 6 peptide ABC transporter, permease protein (sapB) 1900 564 outer peptide ABC transporter, periplasmic-binding protein (sapA) 1903 72 cytoplasm phosphoenolpyruvate carboxylase (ppc) 1905 337 cytoplasm oxidoreductase 1906 624 inner 1 oxidoreductase 1908 323 inner 0 ferrochelatase (hemH) 1913 321 cytoplasm thioredoxin reductase (trxB) 1915 127 cytoplasm thiol peroxidase (tpx) 1917 286 periplasmic phosphoribosylformylglycinamidine synthase (purL) 1919 960 inner 1 phosphoribosylformylglycinamidine synthase (purL) 1923 247 inner 0 lipooligosaccharide biosynthesis protein 1925 172 inner 5 glp protein 1926 235 cytoplasm ribosomal large subunit pseudouridine synthase D 1927 923 inner 1 ATP-dependent helicase (hepA) 1928 249 cytoplasm L-fucose operon activator (fucR) or transcriptional regulator, DeoR family 1929 568 cytoplasm ABC transporter, ATP-binding protein 1932 440 cytoplasm hemoglobin-binding protein 1933 158 cytoplasm hemoglobin-binding protein 1934 140 cytoplasm 3,4-dihydroxy-2-butanone 4-phosphate synthase (ribB) or GTP cyclohydrolase 1935 282 inner 1 lipooligosaccharide biosynthesis protein or lacto-N-neotetraose biosynthesis glycosyl 1936 160 cytoplasm rRNA methylase 1938 355 cytoplasm signal recognition particle-docking protein FtsY (ftsY) 1939 622 inner 9 O-antigen acetylase 1940 380 cytoplasm ribonuclease D (rnd) 1941 562 inner 2 long chain fatty acid coenzyme A ligase (fadD) 1942 183 lipo outer membrane protein 1944 158 cytoplasm ATP-dependent helicase (dinG) 1949 357 cytoplasm hemagglutinin/hemolysin-related protein 1950 270 cytoplasm traN-related protein 1953 232 outer outer membrane protein P2 (ompP2) 1954 366 cytoplasm queuosine biosynthesis protein (queA) or S-adenosylmethionine:tRNA 1958 1392 outer Adhesion and penetration protein 1959 504 cytoplasm excinuclease ABC, subunit A (uvrA) 1960 220 inner 1 excinuclease ABC, subunit A (uvrA) 1962 384 outer membrane-bound lytic murein transglycosylase A 1963 261 inner 1 HesA/MoeB/ThiF family protein 1965 333 periplasmic adhesin 1967 467 inner 1 NMB1183 1969 156 cytoplasm transcriptional regulator (ttk) 1971 224 cytoplasm catabolite gene activator (crp) 1972 392 cytoplasm tRNA (uracil-5-)-methyltransferase trmA 1973 351 cytoplasm beta-hexosaminidase (exoII) or glycosyl hydrolase, family 3 1975 299 cytoplasm long-chain fatty acid transport protein (fadL) or outer membrane protein P1 1976 189 cytoplasm methylated-DNA--protein-cysteine methyltransferase (dat1) 1977 87 cytoplasm DNA mismatch repair protein (mutH) 1978 53 inner 0 DNA mismatch repair protein (mutH) 1980 71 cytoplasm DNA mismatch repair protein (mutH) 1981 430 inner 1 cell cycle protein (mesJ) 1982 34 cytoplasm pyridoxine kinase 1983 186 cytoplasm acetyl-CoA carboxylase, carboxyl transferase subunit alpha 1984 141 cytoplasm acetyl-CoA carboxylase, carboxyl transferase subunit alpha 1986 261 inner 9 membrane protein 1988 212 cytoplasm ABC transporter, ATP-binding protein (yebM) 1989 127 cytoplasm selenocysteine-specific elongation factor (selB) 1991 55 cytoplasm selenocysteine-specific elongation factor (selB) or translation elongation factor Tu tufA 1992 461 inner 1 L-seryl-tRNA selenium transferase (selA) 1993 861 inner 1 DNA mismatch repair protein (mutS) 1995 74 inner 2 tryptophan-specific transport protein (mtr) 1996 339 inner 5 tryptophan-specific transport protein (mtr) 1997 81 inner 2 ATP synthase F0, subunit a (atpB) 1998 88 inner 1 ATP synthase F0, subunit c (atpE) 1999 156 periplasmic ATP synthase F0, subunit b (atpF) 2000 144 cytoplasm ATP synthase F1, subunit delta (atpH) 2001 41 inner 0 ATP synthase F1, subunit delta (atpH) 2002 513 cytoplasm ATP synthase F1, subunit alpha (atpA) 2003 289 cytoplasm ATP synthase F1, subunit gamma (atpG) 2005 76 inner 1 ATP synthase F1, subunit beta (atpD) 2007 372 cytoplasm ATP synthase F1, subunit beta (atpD) 2008 147 inner 1 ATP synthase F1, subunit epsilon (atpC) 2009 54 inner 1 tyrosine-specific transport protein (tyrP) 2010 117 inner 1 ribosomal protein L20 (rpL20) 2011 77 cytoplasm exodeoxyribonuclease V, beta chain (recB) 2012 1086 cytoplasm exodeoxyribonuclease V, beta chain (recB) 2013 288 cytoplasm exodeoxyribonuclease V, alpha chain (recD) 2014 47 cytoplasm exodeoxyribonuclease V, alpha chain (recD) 2016 194 cytoplasm exodeoxyribonuclease V, alpha chain (recD) 2021 107 cytoplasm virulence associated protein A (vapA) 2022 556 cytoplasm ABC transporter, ATP-binding protein 2028 435 cytoplasm transcription-repair coupling factor (mfd) 2029 228 cytoplasm transcription-repair coupling factor (mfd) 2030 392 cytoplasm transcription-repair coupling factor (mfd) 2031 36 cytoplasm transcription-repair coupling factor (mfd) 2032 86 cytoplasm leucyl-tRNA synthetase (leuS) 2034 688 cytoplasm leucyl-tRNA synthetase (leuS) 2036 281 cytoplasm undecaprenyl diphosphate synthase 2038 288 inner 7 CDP-diglyceride synthetase (cdsA) 2041 283 inner 2 protective surface antigen D15 Omp85 2044 256 cytoplasm RNA polymerase sigma-70 factor (rpoD) 2045 300 cytoplasm RNA polymerase sigma-70 factor (rpoD) 2046 347 cytoplasm DNA primase (dnaG) 2047 191 cytoplasm DNA primase (dnaG) 2048 52 cytoplasm DNA primase (dnaG) 2049 71 cytoplasm ribosomal protein S21 (rpS21) 2050 342 inner 1 O-sialoglycoprotein endopeptidase (gcp) 2051 206 cytoplasm thymidine kinase (tdk) 2052 406 inner 10 tyrosine-specific transport protein (tyrP) or tryptophan transporter mtr 2053 86 cytoplasm ferredoxin, 4Fe—4S bacterial type (fdx-2) 2058 263 cytoplasm phosphoglycerate kinase (pgk) 2059 81 cytoplasm phosphoglycerate kinase (pgk) 2061 207 cytoplasm amino acid ABC transporter, ATP-binding protein 2062 79 inner 0 amino acid ABC transporter, ATP-binding protein 2065 230 inner 4 ribonuclease BN (rbn) 2066 53 cytoplasm ribonuclease BN (rbn) 2070 273 inner 1 uridine phosphorylase (udp) 2071 438 inner 9 transport protein 2073 568 inner 1 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate 2074 185 cytoplasm menaquinone-specific isochorismate synthase (menF) or anthranilate synthase component I trpE 2076 679 cytoplasm excinuclease ABC, subunit B (uvrB) 2079 756 inner 4 malate oxidoreductase 2081 238 inner 5 tyrosine-specific transport protein (tyrP) or tryptophan transporter mtr 2083 228 inner 0 phosphoribosyl-AMP cyclohydrolase/phosphoribosyl-ATP 2084 258 cytoplasm hisF cyclase (hisF) 2085 249 cytoplasm phosphoribosylformimino-5-aminoimidazole carboxamide 2086 199 cytoplasm amidotransferase (hisH) 2087 381 cytoplasm imidazoleglycerol-phosphate dehydratase/ 2088 367 cytoplasm histidinol-phosphate aminotransferase (hisC) 2089 427 inner 1 histidinol dehydrogenase (hisD) 2090 35 cytoplasm ATP phosphoribosyltransferase (hisG) 2091 199 inner 1 biotin operon repressor/biotin acetyl coenzyme A or BirA protein/Bvg accessory factor 2092 488 inner 1 inosine-5′-monophosphate dehydrogenase (guaB) 2094 523 inner 1 GMP synthase (guaA) 2095 296 inner 7 rarD protein 2097 168 inner 0 transcriptional regulator 2099 321 inner 10 Na+/H+ antiporter (nhaA) 2100 32 cytoplasm hemolysin 2101 522 inner 7 apolipoprotein N-acyltransferase (cutE) 2106 193 cytoplasm recombination associated protein RdgC rdgC 2108 105 cytoplasm recombination associated protein RdgC rdgC 2110 290 cytoplasm integrase/recombinase 2115 158 inner 4 colicin V production protein (cvpA) 2118 441 inner 2 acetate kinase (ackA) 2119 331 periplasmic phosphate acetyltransferase (pta) 2120 403 inner 1 phosphate acetyltransferase (pta) 2122 314 inner 1 adenine specific methylase 2123 323 cytoplasm cys regulon transcriptional activator (cysB) 2124 71 cytoplasm phosphoribosylaminoimidazole carboxylase, catalytic subunit 2126 362 inner 1 phosphoribosylaminoimidazole carboxylase, ATPase subunit 2127 396 cytoplasm aspartate aminotransferase (aspC) 2128 220 inner 1 spermidine/putrescine ABC transporter, ATP-binding 2134 152 cytoplasm mercuric resistance operon regulatory protein (merR2) 2138 560 inner 10 PTS system, fructose-specific IIBC component (fruA) 2139 313 cytoplasm 1-phosphofructokinase (fruK) or ADP-heptose synthase 2140 499 cytoplasm PTS system, fructose-specific IIA/FPr component (fruB) 2143 92 cytoplasm virulence associated protein D (vapD) 2146 101 inner 1 hypoxanthine phosphoribosyltransferase (hpt) 2147 451 cytoplasm pmbA protein (pmbA) 2151 241 cytoplasm ABC transporter, ATP-binding protein 2152 164 cytoplasm nitrogen regulatory IIA protein (ptsN) 2155 202 cytoplasm chorismate mutase/prephenate dehydratase (pheA) 2157 148 cytoplasm ABC transporter, ATP-binding protein 2158 192 cytoplasm histidinol-phosphatase 2160 221 cytoplasm 5,10 methylenetetrahydrofolate reductase (metF) 2161 89 cytoplasm dethiobiotin synthase (bioD-1) 2162 313 inner 5 TRK system potassium uptake protein (trkH) or bis(5′-nucleosyl)- tetraphosphatase, symmetrical/Trk 2163 191 inner 3 TRK system potassium uptake protein (trkH) or bis(5′-nucleosyl)- tetraphosphatase, symmetrical/Trk 2166 288 inner 4 heat shock protein (htpX) 2168 130 cytoplasm ribonuclease 2169 244 inner 0 lipoprotein (vacJ) 2172 185 cytoplasm transcription antitermination protein (nusG) 2173 138 inner 3 preprotein translocase SecE subunit (secE) 2175 411 cytoplasm ATP-dependent Clp protease, ATP-binding subunit (clpX) 2176 211 cytoplasm ATP-dependent Clp protease, proteolytic subunit (clpP) 2177 394 cytoplasm trigger factor (tig) 2178 52 cytoplasm trigger factor (tig) 2180 89 cytoplasm ribosomal protein S20 (rpS20) 2181 524 inner 11 virulence factor (mviN) 2182 312 cytoplasm riboflavin kinase/FMN adenylyltransferase (ribF) 2183 484 inner 1 isoleucyl-tRNA synthetase ileS 2184 485 cytoplasm isoleucyl-tRNA synthetase ileS 2185 102 cytoplasm hit-related protein 2186 184 cytoplasm lipoprotein 2187 393 periplasmic penicillin-binding protein 5 (dacA) 2189 212 cytoplasm lipoate biosynthesis protein B (lipB) 2190 320 cytoplasm lipoate biosynthesis protein A (lipA) 2191 335 inner 1 citrate lyase ligase (citC) 2192 95 cytoplasm citrate lyase, gamma chain (citD) 2193 291 inner 0 citrate lyase, beta chain (citE) 2195 500 inner 1 citrate lyase, alpha chain (citF) 2196 416 inner 1 citG protein (citG) 2200 256 inner 1 heme-hemopexin utilization protein A (hxuA) 2202 458 cytoplasm DNA repair protein (radA) 2204 166 inner 1 leucine responsive regulatory protein (lrp) 2205 554 inner 5 cell division protein FtsK ftsK-1 2208 169 cytoplasm polypeptide deformylase (def) 2209 318 inner 1 methionyl-tRNA formyltransferase (fmt) 2211 450 cytoplasm sun protein (sun) or 16S RNA methyltransferase rsmB 2212 458 cytoplasm TRK system potassium uptake protein (trkA) 2213 134 inner 2 large conductance mechanosensitive channel (mscL) 2215 40 cytoplasm RNA polymerase sigma-E factor (rpoE) 2231 347 inner 1 lipopolysaccharide biosynthesis protein or ADP-heptose--LPS heptosyltransferase II rfaF 2232 539 outer heme-hemopexin utilization protein C or iron-regulated outer membrane protein FrpB frpB 2233 170 cytoplasm heme-hemopexin utilization protein C 2234 565 outer heme-hemopexin utilization protein B (hxuB) 2235 758 outer-hand heme-hemopexin utilization protein A (hxuA) 2236 231 cytoplasm DNA ligase ligA-2 2238 327 cytoplasm dipeptide ABC transporter, ATP-binding protein (dppF) 2241 330 cytoplasm dipeptide ABC transporter, ATP-binding protein (dppD) 2242 295 inner 6 dipeptide ABC transporter, permease protein (dppC) or thiol:disulfide interchange protein DsbD dsbD 2243 333 inner 5 dipeptide ABC transporter, permease protein (dppB) 2246 727 cytoplasm DNA helicase II (uvrD) 2249 141 cytoplasm 6-pyruvoyl tetrahydrobiopterin synthase 2250 227 inner 0 aluminum resistance protein 2252 184 cytoplasm branched-chain-amino-acid transaminase (ilvE) 2259 898 inner 1 exodeoxyribonuclease V, gamma chain (recC) 2260 163 cytoplasm exodeoxyribonuclease V, gamma chain (recC) 2262 372 inner 1 riboflavin biosynthesis protein (ribD) 2263 357 inner 1 protease (degS) 2274 192 inner 0 molybdopterin-guanine dinucleotide biosynthesis protein 2277 216 periplasmic periplasmic oxidoreductase (por) or thiol:disulfide interchange protein DsbA dsbA-2 2280 363 cytoplasm tRNA (uracil-5-)-methyltransferase (trmA) 2282 125 inner 1 sigma-E factor regulatory protein 2283 33 cytoplasm sigma-E factor regulatory protein 2285 178 inner 0 molybdopterin-guanine dinucleotide biosynthesis protein B 2289 652 cytoplasm ATP-dependent Clp protease, ATPase subunit (clpB) 2293 156 cytoplasm DNA polymerase I (polA) 2294 785 cytoplasm DNA polymerase I (polA) 2299 507 inner 0 N utilization substance protein A (nusA) 2301 855 cytoplasm translation initiation factor 2 (infB) 2303 466 cytoplasm type I restriction enzyme (hsdR) 2304 285 cytoplasm type I restriction enzyme (hsdR) 2307 518 cytoplasm anthranilate synthase component I (trpE) 2308 195 cytoplasm anthranilate synthase component II (trpG) or para-aminobenzoate synthase glutamine 2311 84 cytoplasm anthanilate phosphoribosyltransferase (trpD) 2313 231 cytoplasm anthanilate phosphoribosyltransferase (trpD) 2314 477 cytoplasm indole-3-glycerol phosphate synthase/ 2317 239 cytoplasm valyl-tRNA synthetase (valS) 2318 425 inner 1 valyl-tRNA synthetase (valS) 2319 35 cytoplasm valyl-tRNA synthetase (valS) 2321 150 cytoplasm valyl-tRNA synthetase (valS) 2322 102 cytoplasm valyl-tRNA synthetase (valS) 2324 42 inner 1 transport protein 2325 238 cytoplasm purine-nucleoside phosphorylase (deoD) or 5-methylthioadenosine 2327 142 inner 0 ribosomal protein L11 (rpL11) 2328 229 cytoplasm ribosomal protein L1 (rpL1) 2329 1298 cytoplasm DNA-directed RNA polymerase, beta chain (rpoB) 2331 158 cytoplasm iron(III) ABC transporter, periplasmic-binding protein 2333 506 inner 11 iron(III) ABC transporter, permease protein (hitB) 2335 356 cytoplasm iron(III) ABC transporter, ATP-binding protein (hitC) 2338 377 cytoplasm succinyl-diaminopimelate desuccinylase (dapE) 2341 631 cytoplasm heat shock protein (htpG) 2344 106 periplasmic organic solvent tolerance protein 2345 667 cytoplasm organic solvent tolerance protein 2346 572 inner 1 prolyl-tRNA synthetase (proS) 2347 630 inner 1 ATP-dependent DNA helicase (recQ) 2348 113 cytoplasm cyaY protein (cyaY) 2350 415 cytoplasm diaminopimelate decarboxylase (lysA) 2351 208 cytoplasm nitrate/nitrite response regulator protein (narP) or transcriptional regulator, LuxR family 2354 203 cytoplasm pseudouridine synthase RluD (rluD) or ribosomal large subunit pseudouridine synthase D 2356 272 lipo lipoprotein or competence lipoprotein ComL comL 2359 246 cytoplasm pyruvate formate-lyase activating enzyme (act) 2360 772 cytoplasm formate acetyltransferase (pfl) 2361 286 inner 6 formate transporter 2365 276 inner 2 sugar kinase 2368 377 inner 5 amino acid carrier protein 2371 158 inner 0 YgbB/YacN family protein 2373 146 cytoplasm mioC protein (mioC) or sulfite reductase (NADPH) flavoprotein, alpha 2376 333 inner 1 glpX protein (glpX) 2381 551 inner 6 ABC transporter, ATP-binding protein 2382 360 inner 2 ATP-binding transport protein (cydD) 2383 228 cytoplasm heat shock protein (grpE) 2385 520 cytoplasm DNA repair protein (recN) 2387 38 cytoplasm DNA repair protein (recN) 2388 981 inner 1 glutamate-ammonia-ligase adenylyltransferase (glnE) 2389 311 cytoplasm tRNA delta(2)-isopentenylpyrophosphate transferase (trpX) 2390 390 cytoplasm DNA mismatch repair protein (mutL) 2391 123 cytoplasm thymidylate synthetase (thyA) 2392 173 cytoplasm cytidine and deoxycytidylate deaminase family 2395 545 cytoplasm preprotein translocase SecA subunit (secA) 2396 363 cytoplasm preprotein translocase SecA subunit (secA) 2397 163 cytoplasm mutator mutT protein (mutT) 2398 618 inner 10 glutathione-regulated potassium efflux system protein (kefC) 2399 254 cytoplasm 3-demethylubiquinone-9 3-methyltransferase ubiG 2401 245 cytoplasm ribosomal protein S2 (rpS2) 2402 71 inner 1 preprotein translocase SecY subunit (secY) 2403 144 cytoplasm ribosomal protein L15 (rpL15) 2404 59 cytoplasm ribosomal protein L30 (rpL30) 2405 267 inner 1 glucosamine--fructose-6-phosphate aminotransferase (glmS) 2406 177 inner 3 disulfide bond formation protein B (dsbB) 2407 238 inner 5 Na+/H+ antiporter (nhaB) 2408 292 inner 5 Na+/H+ antiporter (nhaB) 2410 241 cytoplasm fatty acid metabolism regulator protein (fadR) 2411 455 cytoplasm phosphatidylserine synthase (pssA) or cardiolipin synthetase family protein 2412 201 cytoplasm rRNA methylase 2413 232 cytoplasm adenine specific methylase 2415 122 cytoplasm ATP-dependent RNA helicase SrmB (srmB) 2416 287 cytoplasm ATP-dependent RNA helicase SrmB (srmB) 2417 231 cytoplasm protease 2418 203 cytoplasm ATP phosphoribosyltransferase (hisG) 2421 410 cytoplasm D-3-phosphoglycerate dehydrogenase (serA) 2422 219 inner 1 ribose 5-phosphate isomerase A (rpiA) 2423 383 cytoplasm oxygen-independent coproporphyrinogen III oxidase 2424 658 cytoplasm ATP-dependent proteinase (lon) 2428 298 cytoplasm transcriptional regulator, araC family 2429 38 cytoplasm ABC transporter, ATP-binding protein 2430 576 inner 4 ABC transporter, ATP-binding protein 2432 92 periplasmic mercuric ion scavenger protein (merP) 2433 120 inner 3 mercuric ion transport protein (merT) 2435 472 cytoplasm anaerobic dimethyl sulfoxide reductase, chain A (dmsA) 2436 352 cytoplasm anaerobic dimethyl sulfoxide reductase, chain A (dmsA) 2437 205 cytoplasm anaerobic dimethyl sulfoxide reductase, chain B (dmsB) 2438 279 inner 7 anaerobic dimethyl sulfoxide reductase, chain C (dmsC) 2440 166 cytoplasm ferredoxin-type protein (napF) or NADH dehydrogenase I, I subunit nuol 2443 133 cytoplasm 2-isopropylmalate synthase (leuA) 2445 358 cytoplasm 3-isopropylmalate dehydrogenase (beta-IPM dehydrogenase) 2446 469 cytoplasm 3-isopropylmalate dehydratase, alpha subunit (leuC) 2447 200 inner 0 3-isopropylmalate dehydratase small subunit (leuD) 2448 1794 outer-hand immunoglobin A1 protease (iga1) or IgA-specific serine endopeptidase iga 2449 378 cytoplasm DNA/ATP binding protein (recF) 2450 366 cytoplasm DNA polymerase III, beta subunit (dnaN) 2452 454 cytoplasm chromosomal replication initiator protein (dnaA) 2453 118 cytoplasm transferrin-binding protein 1 precursor (tbp1) 2454 231 cytoplasm transferrin-binding protein 1 precursor (tbp1) 2457 199 inner 1 baseplate assembly protein V 2462 861 cytoplasm tail fibre protein 2476 69 cytoplasm aspartokinase I/homoserine dehydrogenase I (thrA) 2477 307 cytoplasm aspartokinase I/homoserine dehydrogenase I (thrA) 2478 314 inner 1 homoserine kinase (thrB) 2479 425 cytoplasm threonine synthase (thrC) 2480 238 cytoplasm integrase/recombinase (xerC) 2491 176 cytoplasm ferredoxin-type 4Fe—4S protein (napF) 2492 93 cytoplasm napD protein (napD) 2493 832 outer-hand Formate dehydrogenase major subunit 2494 279 cytoplasm ferredoxin-type protein (napG) 2495 287 inner 4 ferredoxin-type 4Fe—4S protein (napH) 2496 150 periplasmic periplasmic nitrate reductase (napB) 2497 200 inner 1 cytochrome C-type protein (napC) 2498 214 inner 0 adenylate kinase (adk) 2499 412 inner 10 permease or AmpG-related protein 2501 241 inner 0 UDP-glucose 4-epimerase (galE) 2502 82 cytoplasm UDP-glucose 4-epimerase (galE) 2504 244 cytoplasm iron(III) ABC transporter, ATP-binding protein fbpC 2505 176 inner 4 ABC transporter, permease protein 2508 241 periplasmic FkbP-type peptidyl-prolyl cis-trans isomerase (fkpA) or macrophage infectivity potentiator 2509 73 cytoplasm slyX protein (slyX) 2511 33 cytoplasm peroxiredoxin 2 family protein/glutaredoxin 2512 48 cytoplasm peroxiredoxin 2 family protein/glutaredoxin 2513 117 cytoplasm peroxiredoxin 2 family protein/glutaredoxin 2514 301 cytoplasm hydrogen peroxide-inducible genes activator (oxyR) or transcriptional regulator, LysR family 2517 158 cytoplasm transcription elongation factor (greB) 2518 770 cytoplasm transcription accessory protein (tex) 2519 736 cytoplasm DNA gyrase, subunit B (gyrB) 2520 59 cytoplasm DNA gyrase, subunit B (gyrB) 2521 234 cytoplasm ribulose-phosphate 3-epimerase (dod) 2522 224 cytoplasm phosphoglycolate phosphatase (gph) 2530 132 cytoplasm transposase 2531 369 inner 8 multidrug resistance protein B (emrB) or fatty acid efflux system protein farB 2532 256 inner 1 cell division protein (ftsN) 2533 1032 inner 12 acriflavine resistance protein (acrB) or multiple transferable resistance system protein MtrD 2534 419 inner 1 lipoprotein or membrane fusion protein mtrC 2535 196 cytoplasm transcriptional repressor (Bm3R1) or trancscriptional regulator MtrR mtrR 2538 418 cytoplasm ATP-dependent RNA helicase (rhlB) 2541 210 periplasmic kinase 2542 421 inner 1 serine hydroxymethyltransferase (serine methylase) (glyA) 2543 478 inner 3 YhbX/YhjW/YijP/YjdB family protein 2544 85 cytoplasm phosphoribosylamine--glycine ligase (purD) 2545 101 inner 1 cell division protein (ftsQ) 2546 306 inner 0 D-alanine--D-alanine ligase (ddlB) 2548 475 inner 2 UDP-N-acetylmuramate--alanine ligase (murC) 2550 351 inner 1 UDP-N-acetylglucosamine--N-acetylmuramyl-(pentapeptide) 2552 394 inner 9 cell division protein (ftsW) 2553 437 cytoplasm UDP-N-acetylmuramoylalanine--D-glutamate ligase (murD) 2554 360 inner 10 phospho-N-acetylmuramoyl-pentapeptide-transferase E (mraY) 2555 457 cytoplasm UDP-MurNAc-pentapeptide synthetase (murF) 2556 488 inner 1 UDP-N-acetylmuramyl-tripeptide synthetase (murE) 2557 610 inner 1 penicillin-binding protein 3 (ftsI) 2558 107 inner 1 cell division protein (ftsL) 2561 208 cytoplasm fuculokinase (fucK) 2564 68 cytoplasm transcriptional regulatory protein (asnC) 2569 269 inner 0 sulfite synthesis pathway protein (cysQ) or inositol monophosphatase family protein 2570 474 inner 0 glucose-6-phosphate 1-dehydrogenase (zwf) 2571 245 cytoplasm oxidoreductase (devB) 2577 392 inner 1 6-phosphogluconate dehydrogenase, decarboxylating (gnd) 2578 76 inner 0 6-phosphogluconate dehydrogenase, decarboxylating (gnd) 2581 275 cytoplasm diadenosine-tetraphosphatase (apaH) or bis(5′-nucleosyl)- tetraphosphatase, symmetrical/Trk 2582 312 cytoplasm lipooligosaccharide biosynthesis protein or lacto-N-neotetraose biosynthesis glycosyl 2583 287 cytoplasm dimethyladenosine transferase (ksgA) 2584 253 cytoplasm lipopolysaccharide glycosyl transferase 2585 65 cytoplasm lipopolysaccharide glycosyl transferase 2586 84 cytoplasm translation initiation factor 1 (infA) 2587 480 inner 8 glycerol-3-phosphatase transporter (glpT) 2588 364 lipo glycerophosphoryl diester phosphodiesterase (glpQ) 2591 217 inner 4 glycerol uptake facilitator protein (glpF) 2592 503 cytoplasm glycerol kinase (glpK) 2593 155 inner 1 xanthine-guanine phosphoribosyltransferase (gptB) 2594 45 cytoplasm glycerophosphoryl diester phosphodiesterase (glpQ) 2595 274 lipo lipoprotein E (hel) 2597 132 inner 1 exopolyphosphatase 2598 212 cytoplasm exopolyphosphatase 2600 133 inner 1 peptide chain release factor 3 (prfC) 2606 309 cytoplasm transcriptional activator (metR) 2610 89 periplasmic pyrroline-5-carboxylate reductase (proC) 2612 189 inner 0 pyrroline-5-carboxylate reductase (proC) 2617 297 cytoplasm integrase/recombinase (xerD) 2619 335 cytoplasm Holliday junction DNA helicase (ruvB) 2620 204 cytoplasm Holliday junction DNA helicase (ruvA) 2621 190 cytoplasm crossover junction endodeoxyribonuclease (ruvC) 2623 156 cytoplasm datP pyrophosphohydrolase (ntpA) 2625 588 cytoplasm aspartyl-tRNA synthetase (aspS) 2629 78 cytoplasm virulence associated protein B (vapB) 2630 134 cytoplasm virulence associated protein C 2631 135 cytoplasm lactoylglutathione lyase (gloA) 2632 229 cytoplasm ribonuclease T (rnt) 2636 188 cytoplasm translation elongation factor P (efp) 2640 431 inner 1 opacity associated protein (oapA) 2641 134 lipo opacity associated protein (oapB) 2642 236 cytoplasm DNA repair protein (recO) 2643 438 cytoplasm tRNA (uracil-5-)-methyltransferase trmA 2644 651 cytoplasm elongation factor G (fusA) 2646 394 cytoplasm elongation factor Tu (tufB) 2647 75 inner 2 chloride channel protein-related protein 2649 245 inner 3 chloride channel protein-related protein 2654 336 cytoplasm tryptophanyl-tRNA synthetase (trpS) 2657 92 cytoplasm adenylosuccinate lyase (purB) 2659 364 cytoplasm adenylosuccinate lyase (purB) 2660 163 cytoplasm ribosomal protein L10 (rpL10) 2661 126 inner 0 ribosomal protein L7/L12 (rpL7/L12) 2663 456 inner 0 UDP-N-acetylglucosamine pyrophosphorylase (glmU) 2665 311 cytoplasm lysophospholipase L2 (pldB) 2666 371 cytoplasm aspartate-semialdehyde dehydrogenase (asd) 2667 243 inner 4 transport protein 2670 136 cytoplasm modulator of drug activity B (mdaB) 2671 42 cytoplasm modulator of drug activity B (mdaB) 2672 676 cytoplasm ATP-dependent DNA helicase (rep) 2674 156 inner 1 lipopolysaccharide core biosynthesis protein (kdtB) 2675 427 inner 2 3-deoxy-d-manno-octulosonic-acid transferase (kdtA) 2676 254 cytoplasm lipopolysaccharide biosynthesis protein or beta-1,4-glucosyltransferase lgtF 2678 192 cytoplasm DNA-3-methyladenine glycosidase I (tagI) 2680 268 inner 1 shikimate 5-dehydrogenase (aroE) 2682 178 cytoplasm DNA topoisomerase I topA 2683 63 cytoplasm ABC transporter, ATP-binding protein 2685 115 cytoplasm anaerobic ribonucleoside-triphosphate reductase (nrdD) 2686 272 cytoplasm anaerobic ribonucleoside-triphosphate reductase (nrdD) 2687 286 cytoplasm acyl-CoA thioesterase II (tesB) 2688 469 cytoplasm cysteinyl-tRNA synthetase (cysS) 2689 169 cytoplasm peptidyl-prolyl cis-trans isomerase B (ppiB) 2698 107 cytoplasm thioredoxin (trxM) 2701 335 inner 1 D-lactate dehydrogenase, fermentative (ldhA) 2702 393 inner 1 cystathionine gamma-synthase (metB) 2703 175 inner 1 ParA family protein 2705 451 periplasmic replicative DNA helicase (dnaB) 2714 140 cytoplasm single-stranded DNA binding protein (ssb) 2717 686 cytoplasm DNA topoisomerase III (topB) 2722 156 cytoplasm DNA repair protein (radC) 2733 150 cytoplasm mutT protein mutT 2735 170 inner 3 transport protein 2736 280 cytoplasm aspartate ammonia-lyase (aspA) 2738 236 periplasmic aspartokinase I/homoserine dehydrogenase I (thrA) 2739 317 cytoplasm transaldolase B (talB) 2740 217 inner 1 glyceraldehyde-3-phosphate dehydrogenase (gapdH) 2741 34 cytoplasm inner membrane protein, 60 kDa (yidC) 2742 204 cytoplasm inner membrane protein, 60 kDa (yidC) 2745 229 cytoplasm sufI protein (sufI) 2747 167 cytoplasm heat shock protein (hslU) or ATP-dependent Clp protease, ATP-binding subunit 2748 94 cytoplasm spermidine/putrescine ABC transporter, periplasmic-binding 2749 287 inner 8 drug resistance translocase family protein 2750 325 inner 2 potassium/copper-transporting ATPase or cation transport ATPase, E1-E2 family 2751 349 cytoplasm 2-oxoglutarate dehydrogenase E1 component (sucA) 2752 34 cytoplasm 2-oxoglutarate dehydrogenase E1 component (sucA) 2755 38 inner 1 serine transporter (sdaC) 2756 217 inner 4 serine transporter (sdaC) 2758 75 lipo thermonuclease family protein 2761 144 cytoplasm orfG protein 2762 51 cytoplasm methionine aminopeptidase (map) 2763 343 cytoplasm protein-PII uridylyltransferase glnD 2764 107 inner 4 transporter 2765 282 inner 5 protein-export membrane protein (secF) 2766 96 cytoplasm recA protein (recA) 2768 152 cytoplasm regulatory protein (recX) 2769 111 lipo crcB protein 2772 163 cytoplasm transcriptional regulatory protein (tyrR) or nitrogen assimilation regulatory protein NtrX ntrX 2774 209 inner 1 glutathione transferase (bphH) or stringent starvation protein A sspA 2780 43 cytoplasm CTP synthetase (pyrG) 2782 138 cytoplasm CTP synthetase (pyrG) 2785 167 cytoplasm transcriptional regulator 2786 93 cytoplasm guanylate kinase (gmk) 2788 88 cytoplasm DNA-directed RNA polymerase, omega chain (rpoZ) 2789 84 cytoplasm guanosine-3′,5′-bis(diphosphate) 3′-pyrophosphohydrolase 2790 38 cytoplasm guanosine-3′,5′-bis(diphosphate) 3′-pyrophosphohydrolase 2792 90 cytoplasm S-adenosylmethionine:2-demethylmenaquinone methyltransferase 2795 120 cytoplasm rbs repressor (rbsR) 2801 113 cytoplasm ferredoxin (fdx-1) or ferredoxin, 2Fe—2S type fdx-2 2807 266 inner 1 modification methylase (hindIIIM) 2811 350 cytoplasm asparaginyl-tRNA synthetase (asnS) or aspartyl-tRNA synthetase aspS 2812 31 cytoplasm riboflavin synthase, beta chain (ribH) 2813 228 inner 3 PqiA family protein 2814 282 inner 1 pqiB protein pqiB 2815 112 cytoplasm asparaginyl-tRNA synthetase (asnS) or aspartyl-tRNA synthetase aspS 2817 128 cytoplasm carbonic anhydrase 2818 122 cytoplasm transcriptional regulatory protein (tyrR) 2825 215 cytoplasm pqiB protein pqiB 2827 194 cytoplasm phosphoheptose isomerase gmhA 2831 233 cytoplasm 28 kDa outer membrane protein (hlpA) 2832 33 cytoplasm glycerol-3-phosphate regulon repressor (glpR)

REFERENCES The Contents of which are Hereby Incorporated by Reference

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1. An isolated, immunogenic polypeptide comprising an amino acid sequence with at least 85% sequence identity to the sequence of SEQ ID NO:1842.
 2. The polypeptide of claim 1, wherein said polypeptide comprises an amino acid sequence with at least 90% sequence identity to the sequence of SEQ ID NO:1842.
 3. The polypeptide of claim 1, wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:1842.
 4. A composition comprising: (a) the polypeptide of claim 1; and (b) a pharmaceutically acceptable carrier.
 5. A composition comprising: (a) the polypeptide of claim 2; and (b) a pharmaceutically acceptable carrier.
 6. A composition comprising: (a) the polypeptide of claim 3; and (b) a pharmaceutically acceptable carrier.
 7. The composition of claim 4, further comprising an adjuvant.
 8. The composition of claim 5, further comprising an adjuvant.
 9. The composition of claim 6, further comprising an adjuvant.
 10. A method of treating or preventing a Haemophilus influenzae infection in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim
 4. 11. A method of treating or preventing a Haemophilus influenzae infection in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim
 5. 12. A method of treating or preventing a Haemophilus influenzae infection in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim
 6. 13. A method of treating or preventing a Haemophilus influenzae infection in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim
 7. 14. A method of treating or preventing a Haemophilus influenzae infection in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim
 8. 15. A method of treating or preventing a Haemophilus influenzae infection in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim
 9. 16. The method of claim 10, wherein the H. influenzae infection is caused by a non-typeable H. influenzae.
 17. The method of claim 11, wherein the H. influenzae infection is caused by a non-typeable H. influenzae.
 18. The method of claim 12, wherein the H. influenzae infection is caused by a non-typeable H. influenzae.
 19. The method of claim 13, wherein the H. influenzae infection is caused by a non-typeable H. influenzae.
 20. The method of claim 14, wherein the H. influenzae infection is caused by a non-typeable H. influenzae.
 21. The method of claim 15, wherein the H. influenzae infection is caused by a non-typeable H. influenzae.
 22. A nucleic acid molecule comprising a cDNA sequence encoding the polypeptide of claim
 1. 23. A nucleic acid molecule comprising a cDNA sequence encoding the polypeptide of claim
 2. 24. A nucleic acid molecule comprising a cDNA sequence encoding the polypeptide of claim
 3. 25. A recombinant vector comprising the nucleic acid molecule of claim
 22. 26. A recombinant vector comprising the nucleic acid molecule of claim
 23. 27. A recombinant vector comprising the nucleic acid molecule of claim
 24. 28. A host cell comprising the recombinant vector of claim
 25. 29. A host cell comprising the recombinant vector of claim
 26. 30. A host cell comprising the recombinant vector of claim
 27. 